This invention is directed to the use of diaryl acid derivatives and their pharmaceutical compositions as PPAR ligand receptor binders. The PPAR ligand receptor binders of this invention are useful as agonists or antagonists of the PPAR receptor.
Peroxisome proliferator-activated receptors (PPAR) can be subdivided into three subtypes, namely: PPARxcex1, PPARxcex4, and PPARxcex3. These are encoded by different genes (Motojima, Cell Structure and Function, 18:267-277, 1993). Moreover, 2 isoforms of PPARxcex3 also exist, PPARxcex31 and xcex32. These 2 proteins differ in their NH2-terminal-30 amino acids and are the result of alternative promoter usage and differential mRNA splicing (Vidal-Puig, Jimenez, Linan, Lowell, Hamann, Hu, Spiegelman, Flier, Moller, J. Clin. Invest., 97:2553-2561, 1996).
Biological processes modulated by PPAR are those modulated by receptors, or receptor combinations, which are responsive to the PPAR receptor ligands described herein. These processes include, for example, plasma lipid transport and fatty acid catabolism, regulation of insulin sensitivity and blood glucose levels, which are involved in hypoglycemia/hyperinsulinism (resulting from, for example, abnormal pancreatic beta cell function, insulin secreting tumors and/or autoimmune hypoglycemia due to autoantibodies to insulin, the insulin receptor, or autoantibodies that are stimulatory to pancreatic beta cells), macrophage differentiation which lead to the formation of atherosclerotic plaques, inflammatory response, carcinogenesis, hyperplasia, adipocyte differentiation.
Obesity is an excessive accumulation of adipose tissue. Recent work in this area indicates that PPARxcex3 plays a central role in the adipocyte gene expression and differentiation. Excess adipose tissue is associated with the development of serious medical conditions, for example, non-insulin-dependent diabetes mellitus (NIDDM), hypertension, coronary artery disease, hyperlipidemia obesity and certain malignancies. The adipocyte may also influence glucose homeostasis through the production of tumor necrosis factor xcex1 (TNFxcex1) and other molecules.
Non-insulin-dependent diabetes mellitus (NIDDM), or Type II diabetes, is the more common form of diabetes, with 90-95% of hyperglycemic patients experiencing this form of the disease. In NIDDM there appears to be a reduction in the pancreatic xcex2-cell mass, several distinct defects in insulin secretion or a decrease in tissue sensitivity to insulin. The symptoms of this form of diabetes include fatigue, frequent urination, thirst, blurred vision, frequent infections and slow healing of sores, diabetic nerve damage and renal disease.
Resistance to the metabolic actions of insulin is one of the key features of non-insulin dependent diabetes (NIDDM). Insulin resistance is characterised by impaired uptake and utilization of glucose in insulin-sensitive target organs, for example, adipocytes and skeletal muscle, and by impaired inhibition of hepatic glucose output. The functional insulin deficiency and the failure of insulin to supress hepatic glucose output results in fasting hyperglycemia. Pancreatic xcex2-cells compensate for the insulin resistance by secreting increased levels of insulin. However, the xcex2-cells are unable to maintain this high output of insulin, and, eventually, the glucose-induced insulin secretion falls, leading to the deterioration of glucose homeostasis and to the subsequent development of overt diabetes.
Hyperinsulinemia is also linked to insulin resistance, hypertriglyceridaemia and increased plasma concentration of low density lipoproteins. The association of insulin resistance and hyperinsulinemia with these metabolic disorders has been termed xe2x80x9cSyndrome Xxe2x80x9d and has been strongly linked to an increased risk of hypertension and coronary artery disease.
Metformin is known in the art to be used in the treatment of diabetes in humans (U.S. Pat. No. 3,174,901). Metformin acts primarily to decrease liver glucose production. Troglitazone(copyright) is known to work primarily on enhancing the ability of skeletal muscle to respond to insulin and take up glucose. It is known that combination therapy comprising metformin and troglitazone can be used in the treatment of abnormalities associated with diabetes (DDT 3:79-88, 1998).
PPAR xcex3 activators, in particular Troglitazone(copyright), have been found to convert cancerous tissue to normal cells in liposarcoma, a tumor of fat (PNAS 96:3951-3956, 1999). Furthermore, it has been suggested that PPAR xcex3 activators may be useful in the treatment of breast and colon cancer (PNAS 95:8806-8811, 1998, Nature Medicine 4:1046-1052, 1998).
Moreover, PPARxcex3 activators, for example Troglitazone(copyright), have been implicated in the treatment of polycystic ovary syndrome (PCO). This is a syndrome in women that is characterized by chronic anovulation and hyperandrogenism. Women with this syndrome often have insulin resistance and an increased risk for the development of noninsulin-dependent diabetes mellitus. (Dunaif, Scott, Finegood, Quintana, Whitcomb, J. Clin. Endocrinol. Metab., 81:3299, 1996.
Furthermore, PPARxcex3 activators have recently been discovered to increase the production of progesterone and inhibit steroidogenesis in granulosa cell cultures and therefore may be useful in the treatment of climacteric. (U.S. Pat. No. 5,814,647 Urban et al. Sep. 29, 1998; B. Lohrke et al. Journal of Edocrinology, 159, 429-39, 1998). Climacteric is defined as the syndrome of endocrine, somatic and psychological changes occurring at the termination of the reproductive period in the female.
Peroxisomes are cellular organelles which play a role in controlling the redox potential and oxidative stress of cells by metabolizing a variety of substrates such as hydrogen peroxide. There are a number of disorders associated with oxidative stress. For example, inflammatory response to tissue injury, pathogenesis of emphysema, ischemia-associated organ injury (shock), doxorubicin-induced cardiac injury, drug-induced hepatotoxicity, atherosclerosis, and hyperoxic lung injuries, are each associated with the production of reactive oxygen species and a change in the reductive capacity of the cell. Therefore, it is envisaged that PPARxcex1 activators, among other things, regulate the redox potential and oxidative stress in cells, would be effective in the treatment of these disorders (Poynter et al, J. Biol. Chem. 273, 32833-41, 1998).
It has also been discovered that PPARxcex1 agonists inhibit NFxcexaB-mediated transcription thereby modulating various inflammatory responses such as the inducible nitric oxide synthase (NOS) and cyclooxygenase-2 (COX-2) enzyme pathways (Pineda-Torra, I. T al, 1999, Curr. Opinion in Lipidology, 10,151-9) and thus can be used in the therapeutic intervention of a wide variety of inflammatory diseases and other pathologies (Colville-Nash, et al., Journal of Immunology, 161, 978-84, 1998; Staels et al, Nature, 393, 790-3, 1998).
Peroxisome proliferators activate PPAR, which in turn, acts as a transcription factor, and causes differentiation, cell growth and proliferation of peroxisomes. PPAR activators are also thought to play a role in hyperplasia and carcinogenesis as well as altering the enzymatic capability of animal cells, such as rodent cells, but these PPAR activators appear to have minimal negative effects in human cells (Green, Biochem. Pharm. 43(3):393, 1992). Activation of PPAR results in the rapid increase of gamma glutamyl transpeptidase and catalase.
PPARxcex1 is activated by a number of medium and long-chain fatty acids and is involved in stimulating xcex2-oxidation of fatty acids in tissues such as liver, heart, skeletal muscle, and brown adipose tissue (Isseman and Green, supra; Beck et al., Proc. R. Soc. Lond. 247:83-87, 1992; Gottlicher et al., Proc. Natl. Acad. Sci. USA 89:4653-4657, 1992). Pharmacological PPARxcex1 activators, for example fenofibrate, clofibrate, genfibrozil, and bezafibrate, are also involved in substantial reduction in plasma triglycerides along with moderate reduction in LDL cholesterol, and they are used particularly for the treatment of hypertriglyceridemia, hyperlipidemia and obesity. PPARxcex1 is also known to be involved in inflammatory disorders. (Schoonjans, K., Current Opionion in Lipidology, 8, 159-66, 1997).
The human nuclear receptor PPARxcex4 has been cloned from a human osteosarcoma cell cDNA library and is fully described in A. Schmidt et al., Molecular Endocrinology, 6:1634-1641 (1992), the contents of which are hereby incorporated herein by reference. It should be noted that PPARxcex4 is also referred to in the literature as PPARxcex2 and as NUC1, and each of these names refers to the same receptor. For example, in A. Schmidt et al., Molecular Endocrinology, 6: pp. 1634-1641, 1992, the receptor is referred to as NUC1. PPARxcex4 is observed in both embryo and adult tissues. This receptor has been reported to be involved in regulating the expression of some fat-specific genes, and plays a role in the adipogenic process (Amri, E. et al., J. Biol. Chem. 270, 2367-71, 1995).
Atherosclerotic disease is known to be caused by a number of factors, for example, hypertension, diabetes, low levels of high density lipoprotein (HDL), and high levels of low density lipoprotein (LDL). In addition to risk reduction via effects on plasma lipid concentrations and other risk factors, PPARxcex1 agonists exert direct atheroprotective effects (Frick, M. H.,et al. 1997.. Circulation 96:2137-2143, de Faire, et al. 1997. Cardiovasc. Drugs Ther. 11 Suppl 1:257-63:257-263).
It has recently been discovered that PPARxcex4 agonists are useful in raising HDL levels and therefore useful in treating atherosclerotic diseases. (Leibowitz et al.; WO/9728149). Atherosclerotic diseases include vascular disease, coronary heart disease, cerebrovascular disease and peripheral vessel disease. Coronary heart disease includes CHD death, myocardial infarction, and coronary revascularization. Cerebrovascular disease includes ischemic or hemorrhagic stroke and transient ischemic attacks.
PPARxcex3 subtypes are involved in activating adipocyte differentiation, and are not involved in stimulating peroxisome proliferation in the liver. Activation of PPARxcex3 is implicated in adipocyte differentiation through the activation of adipocyte-specific gene expression (Lehmann, Moore, Smith-Oliver, Wilkison, Willson, Kliewer, J. Biol. Chem., 270:12953-12956, 1995). The DNA sequences for the PPARxcex3 receptors are described in Elbrecht et al., BBRC 224;431-437 (1996). Although peroxisome proliferators, including fibrates and fatty acids, activate the transcriptional activity of PPAR""s, only prostaglandin J2 derivatives such as the arachidonic acid metabolite 15-deoxy-delta12, 14-prostaglandin J2 (15d-PGJ2) have been identified as natural ligands specific for the PPARxcex3 subtype, which also binds thiazolidinediones.This prostaglandin activates PPARxcex3-dependent adipogenesis, but activates PPARxcex1 only at high concentrations (Forman, Tontonoz, Chen, Brun, Spiegelman, Evans, Cell, 83:803-812, 1995; Kliewer, Lenhard, Wilson, Patel, Morris, Lehman, Cell, 83:813-819, 1995). This is further evidence that the PPAR family subtypes are distinct from one another in their pharmacological response to ligands.
It has been suggested that compounds activating both PPARxcex1 and PPARxcex3 should be potent hypotriglyceridemic drugs, which could be used in the treatment of dyslipidemia associated with atherosclerosis, non-insulin dependent diabetes mellitus,Syndrome X,. (Staels, B. et al., Curr. Pharm. Des., 3 (1), 1-14 (1997)) and familial combined hyperlipidemia (FCH). Syndrome X is the syndrome characterized by an initial insulin resistant state, generating hyperinsulinaemia, dyslipidaemia and impaired glucose tolerance, which can progress to non-insulin dependent diabetes mellitus (Type II diabetes), characterized by hyperglycemia. FCH is characterized by hypercholesterolemia and hypertriglyceridemia within the same patient and family.
The present invention is directed to a series of compounds that are useful in modulating PPAR receptors, as well as to a number of other pharmaceutical uses associated therewith.
This invention provides new aromatic compounds and pharmaceutical compositions prepared therewith that are PPAR ligand receptor binders, and which are useful as agonists or antagonists of the PPAR receptors. The invention also includes the discovery of new uses for previously known compounds.
The compounds for use according to the invention, including the new compounds of the present invention, are of Formula I 
wherein: 
are independently aryl, fused arylcycloalkenyl, fused arylcycloalkyl, fused arylheterocyclenyl, fused arylheterocyclyl, heteroaryl, fused heteroarylcycloalkenyl, fused heteroarylcycloalkyl, fused heteroarylheterocyclenyl, or fused heteroarylheterocyclyl;
A is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR13xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94N(R14)C(O)xe2x80x94, xe2x80x94C(O)N(R15)xe2x80x94, xe2x80x94N(R14)C(O)N(R15)xe2x80x94, xe2x80x94C(R14)xe2x95x90Nxe2x80x94, 
B is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR9xe2x80x94, a chemical bond, xe2x80x94C(O)xe2x80x94, xe2x80x94N(R20)C(O)xe2x80x94, or xe2x80x94C(O)N(R20)xe2x80x94;
E is a chemical bond or an ethylene group;
a is 0-6;
b is 0-4;
c is 0-4;
d is 0-6;
g is 1-5;
h is 1-4;
R1, R3, R5 and R7, are independently hydrogen, halogen, alkyl, carboxyl, alkoxycarbonyl or aralkyl;
R2, R4, R6 and R8, are independently xe2x80x94(CH2)qxe2x80x94X;
q is 0-3;
X is hydrogen, halogen, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, aralkoxy, heteroaralkoxy, carboxyl, alkoxycarbonyl, tetrazolyl, acyl, acylHNSO2xe2x80x94, xe2x80x94SR23, Y1Y2Nxe2x80x94 or Y3Y4NCOxe2x80x94;
Y1 and Y2 are independently hydrogen, alkyl, aryl, aralkyl or heteroaralkyl, or one of Y1 and Y2 is hydrogen or alkyl and the other of Y1 and Y2 is acyl or aroyl;
Y3 and Y4 are independently hydrogen, alkyl, aryl, aralkyl or heteroaralkyl;
Z is R21O2Cxe2x80x94, R21OCxe2x80x94, cyclo-imide, xe2x80x94CN, R21O2SHNCOxe2x80x94, R21O2SHNxe2x80x94, (R21)2NCOxe2x80x94, R21Oxe2x80x942,4-thiazolidinedionyl, or tetrazolyl; and
R19 and R21 are independently hydrogen, alkyl, aryl, cycloalkyl, or aralkyl;
R13, R17, R19 and R23 are independently R22OCxe2x80x94, R22NHOCxe2x80x94, hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, heteroaralkyl, or aralkyl;
R14, R15, R16, R18 and R20 are independently hydrogen, alkyl, aralkyl, carbonyl, or alkoxycarbonyl;
or R14, and R15 taken together with the carbon and nitrogen atoms through which they are linked form a 5 or 6-membered azaheterocyclyl group; or
when a is 2-6, then at least one pair of vicinal R1 radicals taken together with the carbon atoms to which the R1 radicals are linked form a 
xe2x80x83group; or
when b is 2-4, then at least one pair of vicinal R3 radicals taken together with the carbon atoms to which the R3 radicals are linked form a 
xe2x80x83group; or
when c is 2-4, then at least one pair of vicinal R5 radicals taken together with the carbon atoms to which the R5 radicals are linked form a 
xe2x80x83group; or
when d is 2-6, then at least one pair of vicinal R7 radicals taken together with the carbon atoms to which the R7 radicals are linked form a 
xe2x80x83group, or a 5-membered cycloalkyl group; or
when d is 2-6, then at least one pair of non-vicinal R7 radicals taken together with the carbon atoms to which the R7 radicals are linked form a 5-membered cycloalkyl group; or
geminal R5 and R6 radicals taken together with the carbon atom through which these radicals are linked form a 5 membered cycloalkyl group; or
geminal R7 and R8 radicals taken together with the carbon atom through which these radicals are linked form a 5 membered cycloalkyl group; and
R22 is hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, heteroaralkyl, or aralkyl; or
a pharmaceutically acceptable salt thereof, an N-oxide thereof, a hydrate thereof or a solvate thereof.
As employed above and throughout the disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
In the present specification, the term xe2x80x9ccompounds for use according to the inventionxe2x80x9d, and equivalent expressions, are meant to embrace compounds of general Formula (I) as hereinbefore described, which expression includes the prodrugs, the pharmaceutically acceptable salts, and the solvates, e.g. hydrates, where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits. For the sake of clarity, particular instances when the context so permits are sometimes indicated in the text, but these instances are purely illustrative and it is not intended to exclude other instances when the context so permits.
xe2x80x9cProdrugxe2x80x9d means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of Formula (I), including N-oxides thereof. For example an ester of a compound of Formula (I) containing a hydroxy group may be convertible by hydrolysis in vivo to the parent molecule. Alternatively an ester of a compound of Formula (I) containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule.
xe2x80x9cPatientxe2x80x9d includes both human and other mammals.
In the present invention, the moiety 
encompasses both the syn and anti configurations.
xe2x80x9cChemical bondxe2x80x9d means a direct single bond between atoms.
xe2x80x9cAcylxe2x80x9d means an Hxe2x80x94COxe2x80x94 or alkyl-COxe2x80x94 group wherein the alkyl group is as herein described. Preferred acyls contain a lower alkyl. Exemplary acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl and palmitoyl.
xe2x80x9cAlkenylxe2x80x9d means an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be a straight or branched chain having about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have 2 to about 12 carbon atoms in the chain and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkenyl chain. xe2x80x9cLower alkenylxe2x80x9d means about 2 to about 4 carbon atoms in the chain, which may be straight or branched. The alkenyl group is optionally substituted by one or more halo groups. Exemplary alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl and decenyl.
xe2x80x9cAlkoxyxe2x80x9d means an alkyl-Oxe2x80x94 group wherein the alkyl group is as herein described. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and heptoxy.
xe2x80x9cAlkoxycarbonylxe2x80x9d means an alkyl-Oxe2x80x94COxe2x80x94 group, wherein the alkyl group is as herein defined. Exemplary alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, or t-butyloxycarbonyl.
xe2x80x9cAlkylxe2x80x9d means an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups have 1 to about 13 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. xe2x80x9cLower alkylxe2x80x9d means about 1 to about 4 carbon atoms in the chain, which may be straight or branched. The alkyl is optionally substituted with one or more xe2x80x9calkyl group substituentsxe2x80x9d which may be the same or different, and include halo, carboxy, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, alkoxy, alkoxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl, Y1Y2NCOxe2x80x94, wherein Y1 and Y2 are independently hydrogen, alkyl, aryl, aralkyl or heteroaralkyl, or Y1 and Y2 taken together with the nitrogen atom to which Y1 and Y2 are attached form heterocyclyl. Exemplary alkyl groups include methyl, trifluoromethyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, and 3-pentyl. Preferably, the alkyl group substituent is selected from acyl, carboxy, carboxymethyl, methoxycarbonylethyl, benzyloxycarbonylmethyl, and pyridylmethyloxycarbonylmethyl and alkoxycarbonyl.
xe2x80x9cAlkylsulfinylxe2x80x9d means an alkyl-SOxe2x80x94 group wherein the alkyl group is as defined above. Preferred groups are those wherein the alkyl group is lower alkyl.
xe2x80x9cAlkylsulfonylxe2x80x9d means an alkyl-SO2xe2x80x94 group wherein the alkyl group is as defined above. Preferred groups are those wherein the alkyl group is lower alkyl.
xe2x80x9cAlkylthioxe2x80x9d means an alkyl-Sxe2x80x94 group wherein the alkyl group is as defined above. Exemplary alkylthio groups include methylthio, ethylthio, i-propylthio and heptylthio.
xe2x80x9cAralkoxyxe2x80x9d means an aralkyl-Oxe2x80x94 group wherein the aralkyl group is as defined herein. Exemplary aralkoxy groups include benzyloxy and 1- and 2-naphthalenemethoxy.
xe2x80x9cAralkoxycarbonylxe2x80x9d means an aralkyl-Oxe2x80x94COxe2x80x94 group wherein the aralkyl group is as defined herein. An exemplary aralkoxycarbonyl group is benzyloxycarbonyl.
xe2x80x9cAralkylxe2x80x9d means an aryl-alkyl- group wherein the aryl and alkyl groups are as defined herein. Preferred aralkyls contain a lower alkyl moiety. Exemplary aralkyl groups include benzyl, 2-phenethyl and naphthalenemethyl.
xe2x80x9cAralkylsulfonylxe2x80x9d means an aralkyl-SO2xe2x80x94 group wherein the aralkyl group is as defined herein.
xe2x80x9cAralkylsulfinylxe2x80x9d means an aralkyl-SOxe2x80x94 group wherein the aralkyl group is as defined herein.
xe2x80x9cAralkylthioxe2x80x9d means an aralkyl-Sxe2x80x94 group wherein the aralkyl group is as defined herein. An exemplary aralkylthio group is benzylthio.
xe2x80x9cAroylxe2x80x9d means an aryl-COxe2x80x94 group wherein the aryl group is as defined herein. Exemplary aroyl groups include benzoyl and 1- and 2-naphthoyl.
xe2x80x9cArylxe2x80x9d means an aromatic monocyclic or multicyclic ring system of about 6 to about 14 carbon atoms, preferably of about 6 to about 10 carbon atoms. The aryl is optionally substituted with one or more xe2x80x9cring system substituentsxe2x80x9d which may be the same or different, and are as defined herein. Exemplary aryl groups include phenyl, naphthyl, substituted phenyl, and substituted naphthyl.
xe2x80x9cAryldiazoxe2x80x9d means an aryl-diazo- group wherein the aryl and diazo groups are as defined herein.
xe2x80x9cFused arylcycloalkenylxe2x80x9d means a fused aryl and cycloalkenyl as defined herein. Preferred fused arylcycloalkenyls are those wherein the aryl thereof is phenyl and the cycloalkenyl consists of about 5 to about 6 ring atoms. A fused arylcycloalkenyl group may be bonded to the rest of the compound through any atom of the fused system capable of such bondage. The fused arylcycloalkenyl may be optionally substituted by one or more ring system substituents, wherein the xe2x80x9cring system substituentxe2x80x9d is as defined herein. Exemplary fused arylcycloalkenyl groups include 1,2-dihydronaphthylenyl; indenyl; 1,4-naphthoquinonyl, and the like.
xe2x80x9cFused arylcycloalkylxe2x80x9d means a fused aryl and cycloalkyl as defined herein. Preferred fused arylcycloalkyls are those wherein the aryl thereof is phenyl and the cycloalkyl consists of about 5 to about 6 ring atoms. A fused arylcycloalkyl group may be bonded to the rest of the compound through any atom of the fused system capable of such bonding. The fused arylcycloalkyl may be optionally substituted by one or more ring system substituents, wherein the xe2x80x9cring system substituentxe2x80x9d is as defined herein. Exemplary fused arylcycloalkyl groups include 1,2,3,4-tetrahydronaphthylenyl; 1,4-dimethyl-2,3-dihydronaphthalenyl; 2,3-dihydro-1,4-naphthoquinonyl, xcex1-tetralonyl, and the like.
xe2x80x9cFused arylheterocyclenylxe2x80x9d means a fused aryl and heterocyclenyl wherein the aryl and heterocyclenyl groups are as defined herein. Preferred fused arylheterocyclenyl groups are those wherein the aryl thereof is phenyl and the heterocyclenyl consists of about 5 to about 6 ring atoms. A fused arylheterocyclenyl group may be bonded to the rest of the compound through any atom of the fused system capable of such bonding. The designation of aza, oxa or thia as a prefix before the heterocyclenyl portion of the fused arylheterocyclenyl means that a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. The fused arylheterocyclenyl may be optionally substituted by one or more ring system substituents, wherein the xe2x80x9cring system substituentxe2x80x9d is as defined herein. The nitrogen atom of a fused arylheterocyclenyl may be a basic nitrogen atom. The nitrogen or sulphur atom of the heterocyclenyl portion of the fused arylheterocyclenyl is also optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Exemplary fused arylheterocyclenyl include 3H-indolinyl, 2(1H)quinolinonyl, 2H-1-oxoisoquinolyl, 1,2-dihydroquinolinyl, (2H)quinolinyl N-oxide, 3,4-dihydroquinolinyl, 1,2-dihydroisoquinolinyl, 3,4-dihydroisoquinolinyl, chromonyl, 3,4-dihydroisoquinoxalinyl, 4-(3H)quinazolinonyl, 4H-chromen-2yl, and the like. Preferably, 2(1H)quinolinonyl, 1,2-dihydroquinolinyl, (2H)quinolinyl N-oxide, or 4-(3H)quinazolinonyl.
xe2x80x9cFused arylheterocyclylxe2x80x9d means a fused aryl and heterocyclyl wherein the aryl and heterocyclyl groups are as defined herein. Preferred fused arylheterocyclyls are those wherein the aryl thereof is phenyl and the heterocyclyl consists of about 5 to about 6 ring atoms. A fused arylheterocyclyl may be bonded to the rest of the compound through any atom of the fused system capable of such bonding. The designation of aza, oxa or thia as a prefix before the heterocyclyl portion of the fused arylheterocyclyl means that a nitrogen, oxygen or sulphur atom respectively is present as a ring atom. The fused arylheterocyclyl group may be optionally substituted by one or more ring system substituents, wherein the xe2x80x9cring system substituentxe2x80x9d is as defined herein. The nitrogen atom of a fused arylheterocyclyl may be a basic nitrogen atom. The nitrogen or sulphur atom of the heterocyclyl portion of the fused arylheterocyclyl is also optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Exemplary fused arylheterocyclyl ring systems include indolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 1H-2,3-dihydroisoindol-2-yl, 2,3-dihydrobenz[f]isoindol-2-yl, 1,2,3,4-tetrahydrobenz[g]isoquinolin-2-yl, chromanyl, isochromanonyl, 2,3-dihydrochromonyl, 1,4-benzodioxan, 1,2,3,4-tetrahydroquinoxalinyl, and the like. Preferably, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinoxalinyl, and 1,2,3,4-tetrahydroquinolinyl.
xe2x80x9cAryloxyxe2x80x9d means an aryl-Oxe2x80x94 group wherein the aryl group is as defined herein. Exemplary groups include phenoxy and 2-naphthyloxy.
xe2x80x9cAryloxycarbonylxe2x80x9d means an aryl-Oxe2x80x94COxe2x80x94 group wherein the aryl group is as defined herein. Exemplary aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl.
xe2x80x9cArylsulfonylxe2x80x9d means an aryl-SO2xe2x80x94 group wherein the aryl group is as defined herein.
xe2x80x9cArylsulfinylxe2x80x9d means an aryl-SOxe2x80x94 group wherein the aryl group is as defined herein.
xe2x80x9cArylthioxe2x80x9d means an aryl-Sxe2x80x94 group wherein the aryl group is as defined herein. Exemplary arylthio groups include phenylthio and naphthylthio.
xe2x80x9cCarbamoylxe2x80x9d is an NH2xe2x80x94COxe2x80x94 group.
xe2x80x9cCarboxyxe2x80x9d means a HO(O)Cxe2x80x94 (carboxylic acid) group.
xe2x80x9cCompounds of the invention,xe2x80x9d and equivalent expressions, are meant to embrace compounds of general Formula (I) as hereinbefore described, which expression includes the prodrugs, the pharmaceutically acceptable salts, and the solvates, e.g. hydrates, where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits. For the sake of clarity, particular instances when the context so permits are sometimes indicated in the text, but these instances are purely illustrative and it is not intended to exclude other instances when the context so permits.
xe2x80x9cCycloalkoxyxe2x80x9d means an cycloalkyl-Oxe2x80x94 group wherein the cycloalkyl group is as defined herein. Exemplary cycloalkoxy groups includc cyclopentyloxy and cyclohexyloxy.
xe2x80x9cCycloalkyl-alkoxyxe2x80x9d means an cycloalkyl-alkylene-Oxe2x80x94 group wherein the cycloalkyl group and alkylene group are as defined herein. Exemplary cycloalkyl-alkoxy groups include cyclopentylmethylene-oxy and cyclohexylmethylene-oxy.
xe2x80x9cCycloalkenylxe2x80x9d means a non-aromatic mono- or multicyclic ring system of about 3 to about 10 carbon atoms, preferably of about 5 to about 10 carbon atoms, and which contains at least one carbon-carbon double bond. Preferred ring sizes of rings of the ring system include about 5 to about 6 ring atoms. The cycloalkenyl is optionally substituted with one or more xe2x80x9cring system substituentsxe2x80x9d which may be the same or different, and are as defined herein. Exemplary monocyclic cycloalkenyl include cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like. An exemplary multicyclic cycloalkenyl is norbornylenyl.
xe2x80x9cCycloalkylxe2x80x9d means a non-aromatic mono- or multicyclic ring system of about 3 to about 10 carbon atoms, preferably of about 5 to about 10 carbon atoms. Preferred ring sizes of rings of the ring system include about 5 to about 6 ring atoms. The cycloalkyl is optionally substituted with one or more xe2x80x9cring system substituentsxe2x80x9d which may be the same or different, and are as defined herein. Exemplary monocyclic cycloalkyl include cyclopentyl, cyclohexyl, cycloheptyl, and the like. Exemplary multicyclic cycloalkyl include 1-decalin, norbornyl, adamant-(1- or 2-)yl, and the like.
xe2x80x9cCycloalkylenexe2x80x9d means a bivalent, saturated carbocyclic group having about 3 to about 6 carbon atoms. Preferred cycloalkylene groups include 1,1-, 1,2-, 1,3-, and 1,4-cis or trans-cyclohexylene, and 1,1-, 1,2-, and 1,3-cyclopentylene.
xe2x80x9cCyclo-imidexe2x80x9d means a compound of formulae 
The cyclo-imide moiety may be attached to the parent molecule through either a carbon atom or nitrogen atom of the carbamoyl moiety. An exemplary imide group is N-phthalimide.
xe2x80x9cDiazoxe2x80x9d means a bivalent xe2x80x94Nxe2x95x90Nxe2x80x94 radical.
xe2x80x9cHaloxe2x80x9d means fluoro, chloro, bromo, or iodo. Preferred are fluoro, chloro and bromo, more preferably fluoro and chloro.
xe2x80x9cHaloxe2x80x9d means fluoro, chloro, bromo, or iodo. Preferred are fluoro, chloro and bromo, more preferably fluoro and chloro.
xe2x80x9cHeteroaralkylxe2x80x9d means a heteroaryl-alkyl- group wherein the heteroaryl and alkyl groups are as defined herein. Preferred heteroaralkyls contain a lower alkyl moiety. Exemplary heteroaralkyl groups include thienylmethyl, pyridylmethyl, imidazolylmethyl and pyrazinylmethyl.
xe2x80x9cHeteroaralkylthioxe2x80x9d means a heteroaralkyl-Sxe2x80x94 group wherein the heteroaralkyl group is as defined herein. An exemplary heteroaralkylthio group is 3-pyridinepropanthiol.
xe2x80x9cHeteroaralkoxyxe2x80x9d means an heteroaralkyl-Oxe2x80x94 group wherein the heteroaralkyl group is as defined herein. An exemplary heteroaralkoxy group is 4-pyridylmethyloxy.
xe2x80x9cHeteroaroylxe2x80x9d means an means an heteroaryl-COxe2x80x94 group wherein the heteroaryl group is as defined herein. Exemplary heteroaryl groups include thiophenoyl, nicotinoyl, pyrrol-2-ylcarbonyl and 1- and 2-naphthoyl and pyridinoyl.
xe2x80x9cHeteroaryldiazoxe2x80x9d means an heteroaryl-diazo- group wherein the heteroaryl and diazo groups are as defined herein.
xe2x80x9cHeteroarylxe2x80x9d means an aromatic monocyclic or multicyclic ring system of about 5 to about 14 carbon atoms, preferably about 5 to about 10 carbon atoms, in which at least one of the carbon atoms in the ring system is replaced by a hetero atom, i.e., other than carbon, for example nitrogen, oxygen or sulfur. Preferred ring sizes of rings of the ring system include about 5 to about 6 ring atoms. The heteroaryl ring is optionally substituted by one or more xe2x80x9cring system substituentsxe2x80x9d which may be the same or different, and are as defined herein. The designation of aza, oxa or thia as a prefix before the heteroaryl means that a nitrogen, oxygen or sulfur atom is present, respectively, as a ring atom. A nitrogen atom of an heteroaryl may be a basic nitrogen atom and also may be optionally oxidized to the corresponding N-oxide. Exemplary heteroaryl and substituted heteroaryl groups include pyrazinyl, thienyl, isothiazolyl, oxazolyl, pyrazolyl, cinnolinyl, pteridinyl, benzofuryl, furazanyl, pyrrolyl, 1,2,4-thiadiazolyl, pyridazinyl, indazolyl, quinoxalinyl, phthalazinyl, imidazo[l,2-a]pyridine, imidazo[2,1-b]thiazolyl, benzofurazanyl, azaindolyl, benzimidazolyl, benzothienyl, thienopyridyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, naphthyridinyl, benzoazaindole, 1,2,4-triazinyl, benzothiazolyl, furyl, imidazolyl, indolyl, isoindolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl. Preferred heteroaryl and substituted heteroaryl groups include quinolinyl, indazolyl, indolyl, quinazolinyl, pyridyl, pyrimidinyl, furyl, benzothiazolyl, quinoxalinyl, benzimidazolyl, benzothienyl, and isoquinolinyl.
xe2x80x9cFused heteroarylcycloalkenylxe2x80x9d means a fused heteroaryl and cycloalkenyl wherein the heteroaryl and cycloalkenyl groups are as defined herein. Preferred fused heteroarylcycloalkenyls are those wherein the heteroaryl thereof is phenyl and the cycloalkenyl consists of about 5 to about 6 ring atoms. A fused heteroarylcycloalkenyl may be bonded to the rest of the compound through any atom of the fused system capable of such bonding. The designation of aza, oxa or thia as a prefix before the heteroaryl portion of the fused heteroarylcycloalkenyl means that a nitrogen, oxygen or sulfur atom is present, respectively, as a ring atom. The fused heteroarylcycloalkenyl may be optionally substituted by one or more ring system substituents, wherein the xe2x80x9cring system substituentxe2x80x9d is as defined herein. The nitrogen atom of a fused heteroarylcycloalkenyl may be a basic nitrogen atom. The nitrogen atom of the heteroaryl portion of the fused heteroarylcycloalkenyl may also be optionally oxidized to the corresponding N-oxide. Exemplary fused heteroarylcycloalkenyl groups include 5,6-dihydroquinolyl; 5,6-dihydroisoquinolyl; 5,6-dihydroquinoxalinyl; 5,6-dihydroquinazolinyl; 4,5-dihydro-1H-benzimidazolyl; 4,5-dihydrobenzoxazolyl; 1,4-naphthoquinolyl, and the like.
xe2x80x9cFused heteroarylcycloalkylxe2x80x9d means a fused heteroaryl and cycloalkyl wherein the heteraryl and cycloalkyl groups are as defined herein. Preferred fused heteroarylcycloalkyls are those wherein the heteroaryl thereof consists of about 5 to about 6 ring atoms and the cycloalkyl consists of about 5 to about 6 ring atoms. A fused heteroarylcycloalkyl may be bonded to the rest of the compoun through any atom of the fused system capable of such bonding. The designation of aza, oxa or thia as a prefix before the heteroaryl portion of the fused heteroarylcycloalkyl means that a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. The fused heteroarylcycloalkyl may be optionally substituted by one or more ring system substituents, wherein the xe2x80x9cring system substituentxe2x80x9d is as defined herein. The nitrogen atom of a fused heteroarylcycloalkyl may be a basic nitrogen atom. The nitrogen atom of the heteroaryl portion of the fused heteroarylcycloalkyl may also be optionally oxidized to the corresponding N-oxide. Exemplary fused heteroarylcycloalkyl include 5,6,7,8-tetrahydroquinolinyl; 5,6,7,8-tetrahydroisoquinolyl; 5,6,7,8-tetrahydroquinoxalinyl; 5,6,7,8-tetrahydroquinazolyl; 4,5,6,7-tetrahydro-1H-benzimidazolyl; 4,5 ,6,7-tetrahydrobenzoxazolyl; 1H-4-oxa-1,5-diazanaphthalen-2-only; 1,3-dihydroimidizole-[4,5]-pyridin-2-onyl, 2,3-dihydro-1,4-dinaphthoquinonyl and the like, preferably, 5,6,7,8-tetrahydroquinolinyl or 5,6,7,8-tetrahydroisoquinolyl.
xe2x80x9cFused heteroarylheterocyclenylxe2x80x9d means a fused heteroaryl and heterocyclenyl wherein the heteraryl and heterocyclenyl groups are as defined herein. Preferred fused heteroarylheterocyclenyls are those wherein the heteroaryl thereof consists of about 5 to about 6 ring atoms and the heterocyclenyl consists of about 5 to about 6 ring atoms. A fused heteroarylheterocyclenyl may be bonded to the rest of the compound through any atom of the fused system capable of such bonding. The designation of aza, oxa or thia as a prefix before the heteroaryl or heterocyclenyl portion of the fused heteroarylheterocyclenyl means that a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. The fused heteroarylheterocyclenyl may be optionally substituted by one or more ring system substituent, wherein the xe2x80x9cring system substituentxe2x80x9d is as defined herein. The nitrogen atom of a fused heteroarylazaheterocyclenyl may be a basic nitrogen atom. The nitrogen or sulphur atom of the heteroaryl or heterocyclenyl portion of the fused heteroarylheterocyclenyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Exemplary fused heteroarylheterocyclenyl groups include 7,8-dihydro[1,7]naphthyridinyl; 1,2-dihydro[2,7]naphthyridinyl; 6,7-dihydro-3H-imidazo[4,5-c]pyridyl; 1,2-dihydro-1,5-naphthyridinyl; 1,2-dihydro-1,6-naphthyridinyl; 1,2-dihydro-1,7-naphthyridinyl; 1,2-dihydro-1,8-naphthyridinyl; 1,2-dihydro-2,6-naphthyridinyl, and the like.
xe2x80x9cFused heteroarylheterocyclylxe2x80x9d means a fused heteroaryl and heterocyclyl wherein the heteroaryl and heterocyclyl groups are as defined herein. Preferred fused heteroarylheterocyclyls are those wherein the heteroaryl thereof consists of about 5 to about 6 ring atoms and the heterocyclyl consists of about 5 to about 6 ring atoms. A fused heteroarylheterocyclyl may be bonded to the rest of the compound through any atom of the fused system capable of such bonding. The designation of aza, oxa or thia as a prefix before the heteroaryl or heterocyclyl portion of the fused heteroarylheterocyclyl means that a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. The fused heteroarylheterocyclyl may be optionally substituted by one or more ring system substituent, wherein the xe2x80x9cring system substituentxe2x80x9d is as defined herein. The nitrogen atom of a fused heteroarylheterocyclyl may be a basic nitrogen atom. The nitrogen or sulphur atom of the heteroaryl or heterocyclyl portion of the fused heteroarylheterocyclyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Exemplary fused heteroarylheterocyclyl groups include 2,3-dihydro-1H pyrrol[3,4-b]quinolin-2-yl; 1,2,3,4-tetrahydrobenz[b][1,7]naphthyridin-2-yl; 1,2,3,4-tetrahydrobenz[b][1,6]naphthyridin-2-yl; 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-2yl; 1,2,3,4-tetrahydro-9H-pyrido[4,3-b]indol-2yl, 2,3,-dihydro-1H-pyrrolo[3,4-b]indol-2-yl; 1H-2,3,4,5-tetrahydroazepino[3,4-b]indol-2-yl; 1H-2,3,4,5-tetrahydroazepino[3,4-b]indol-3-yl; 1H-2,3,4,5-tetrahydroazepino[4,5-b]indol-2yl, 5,6,7,8-tetrahydro[1,7]napthyridinyl; 1,2,3,4-tetrhydro[2,7]naphthyridyl; 2,3-dihydro[1,4]dioxino[2,3-b]pyridyl; 2,3-dihydro[1,4]dioxino[2,3-b]pryidyl; 3,4-dihydro-2H-1-oxa[4,6]diazanaphthalenyl; 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridyl; 6,7-dihydro[5,8]diazanaphthalenyl; 1,2,3,4-tetrahydro[1,5]napthyridinyl; 1,2,3,4-tetrahydro[1,6]napthyridinyl; 1,2,3,4-tetrahydro[1,7]napthyridinyl; 1,2,3,4-tetrahydro[1,8]napthyridinyl; 1,2,3,4-tetrahydro[2,6]napthyridinyl, and the like.
xe2x80x9cHeteroarylsulfonylxe2x80x9d means an heteroaryl-SO2xe2x80x94 group wherein the heteroaryl group is as defined herein. An examplary heterarylsulfonyl groups is 3-pyridinepropansulfonyl.
xe2x80x9cHeteroarylsulfinylxe2x80x9d means an heteroaryl-SOxe2x80x94 group wherein the heteroaryl group is as defined herein.
xe2x80x9cHeteroarylthioxe2x80x9d means an heteroaryl-Sxe2x80x94 group wherein the heteroaryl group is as defined herein. Exemplary heteroaryl thio groups include pyridylthio and quinolinylthio.
xe2x80x9cHeterocyclenylxe2x80x9d means a non-aromatic monocyclic or multicyclic hydrocarbon ring system of about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms, in which at least one or more of the carbon atoms in the ring system is replaced by a hetero atom, for example a nitrogen, oxygen or sulfur atom, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. Preferred ring sizes of rings of the ring system include about 5 to about 6 ring atoms. The designation of aza, oxa or thia as a prefix before the heterocyclenyl means that a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. The heterocyclenyl may be optionally substituted by one or more ring system substituents, wherein the xe2x80x9cring system substituentxe2x80x9d is as defined herein. The nitrogen atom of an heterocyclenyl may be a basic nitrogen atom. The nitrogen or sulphur atom of the heterocyclenyl is also optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Exemplary monocyclic azaheterocyclenyl groups include 1,2,3,4-tetrahydrohydropyridine, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine, 1,4,5,6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, and the like. Exemplary oxaheterocyclenyl groups include 3,4-dihydro-2H-pyran, dihydrofuryl, and fluorodihydrofuryl An exemplary multicyclic oxaheterocyclenyl group is 7-oxabicyclo[2.2.1]heptenyl. Exemplary monocyclic thiaheterocycleny rings include dihydrothiophenyl and dihydrothiopyranyl.
xe2x80x9cHeterocyclylxe2x80x9d means a non-aromatic saturated monocyclic or multicyclic ring system of about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms, in which at least one of the carbon atoms in the ring system is replaced by a hetero atom, for example nitrogen, oxygen or sulfur. Preferred ring sizes of rings of the ring system include about 5 to about 6 ring atoms. The designation of aza, oxa or thia as a prefix before the heterocyclyl means that a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. The heterocyclyl may be optionally substituted by one or more xe2x80x9cring systenm substituentsxe2x80x9d which may be the same or different, and are as defined herein. The nitrogen atom of an heterocyclyl may be a basic nitrogen atom. The nitrogen or sulphur atom of the heterocyclyl is also optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Exemplary monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuryl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like. Exemplary multicyclic heterocyclyl rings include 1,4diazabicyclo-[2.2.2]octane and 1,2-cyclohexanedicarboxylic acid anhydride.
xe2x80x9cRing system substituentxe2x80x9d includes hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, aryloxy, aralkoxy, cycloalkylalkyloxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, fused cycloalkyl, fused cycloalkenyl, fused heterocyclyl, fused heterocyclenyl, arylazo, heteroarylazo, RaRbNxe2x80x94, RcRdNCOxe2x80x94, RcO2CNxe2x80x94, and RcRdNSO2xe2x80x94 wherein Ra and Rb are independently hydrogen, alkyl, aryl, aralkyl or heteroaralkyl, or one of Ra and Rb is hydrogen or alkyl and the other of Ra and Rb is aroyl or heteroaroyl. Rc and Rd are independently hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aralkyl or heteroaralkyl. Where the ring is cycloalkyl, cycloalkenyl, heterocyclyl or heterocyclenyl, the ring system substituent may also include methylene (H2Cxe2x95x90), oxo (Oxe2x95x90), thioxo (Sxe2x95x90), on carbon atom(s) thereof. Preferably, the ring substituents are selected from oxo (Oxe2x95x90), alkyl, aryl, alkoxy, aralkoxy, halo, carboxy, alkoxycarbonyl, and RcO2CNxe2x80x94, wherein Rc is cycloalkyl.
xe2x80x9cTetrazolylxe2x80x9d means a group of formula 
wherein the hydrogen atom thereof is optionally replaced by alkyl, carboxyalkyl or alkoxycarbonylalkyl.
xe2x80x9cPPAR ligand receptor binderxe2x80x9d means a ligand which binds to the PPAR receptor. PPAR ligand receptor binders of this invention are useful as agonists or antagonists of the PPAR-xcex1, PPAR-xcex4, or PPAR-xcex3 receptor.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention. A salt can be prepared in situ during the final isolation and purification of a compound or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate, laurylsulphonate salts, and the like. (See, for example S. M. Berge, et al., xe2x80x9cPharmaceutical Salts,xe2x80x9d J. Pharm. Sci., 66: 1-19, 1977, the contents of which are hereby incorporated herein by reference.)
xe2x80x9cTreatingxe2x80x9d means the partial or complete relieving or preventing of one or more physiological or biochemical parameters associated with PPAR activity.
The term xe2x80x9cmodulatexe2x80x9d refers to the ability of a compound to either directly (by binding to the receptor as a ligand) or indirectly (as a precursor for a ligand or an inducer which promotes production of a ligand from a precursor) induce expression of gene(s) maintained under hormone control, or to repress expression of gene(s) maintained under such control.
The term xe2x80x9cobesityxe2x80x9d refers generally to individuals who are at least about 20-30% over the average weight for the person""s age, sex and height. Technically, xe2x80x9cobesexe2x80x9d is defined, for males, as individuals whose body mass index is greater than 27.3 kg/m2. Those skilled in the art readily recognize that the invention method is not limited to those who fall within the above criteria. Indeed, the invention method can also be advantageously practiced by individuals who fall outside of these traditional criteria, for example by those who are prone to obesity.
The phrase xe2x80x9camount effective to lower blood glucose levelsxe2x80x9d refers to levels of a compound sufficient to provide circulating concentrations high enough to accomplish the desired effect. Such a concentration typically falls in the range of about 10 nM up to 2 xcexcM, with concentrations in the range of about 100 nm up to about 500 nM being preferred.
The phrase xe2x80x9camount effective to lower triclyceride levelsxe2x80x9d refers to levels of a compound sufficient to provide circulating concentrations high enough to accomplish the desired effect. Such a concentration typically falls in the range of about 10 nM up to 2 xcexcM; with concentrations in the range of about 100 nm up to about 500 nM being preferred.
Preferred embodiments according to the invention includes the use of compounds of Formula I (and their pharmaceutical compositions) as binders for PPAR receptors.
More particularly, the use of compounds of Formula I that bind to the PPAR-xcex1 receptor,
compounds of Formula I that bind to the PPAR-xcex4 receptor,
compounds of Formula I that bind to the PPAR-xcex3 receptor,
compounds of Formula I that bind to the PPAR-xcex1 and the PPAR-xcex3 receptor,
compounds of Formula I that bind to the PPAR-xcex1 and the PPAR-xcex4 receptor,
compounds of Formula I that bind to the PPAR-xcex3 and the PPAR-xcex4 receptor,
compounds of Formula I that act as PPAR receptor agonists,
compounds of Formula I that act as PPAR-xcex1 receptor agonists,
compounds of Formula I that act as PPAR-xcex4 receptor agonists,
compounds of Formula I that act as PPAR-xcex3 receptor agonists,
compounds of Formula I that act as both PPAR-xcex1 and PPAR-xcex3 receptor agonists,
compounds of Formula I that act as both PPAR-xcex1 and PPAR-xcex4 receptor agonists,
compounds of Formula I that act as both PPAR-xcex3 and PPAR-xcex4 receptor agonists,
compounds of Formula I that act as both PPAR-xcex1 receptor antagonists and PPAR-xcex3 receptor agonists,
compounds of Formula I that act as both PPAR-xcex1 receptor antagonists and PPAR-xcex4 receptor agonists,
compounds of Formula I and act as both PPAR-xcex3 receptor antagonists and PPAR-xcex4 receptor agonists,
compounds of Formula I that act as both PPAR-xcex1 receptor agonists and PPAR-xcex3 receptor antagonists,
compounds of Formula I that act as both PPAR-xcex1 receptor agonists and PPAR-xcex4 receptor antagonists,
compounds of Formula I that act as both PPAR-xcex3 receptor agonists and PPAR-xcex4 receptor antagonists,
compounds of Formula I that act as PPAR receptor antagonists,
compounds of Formula I that act as PPAR-xcex1 receptor antagonists,
compounds of Formula I that act as PPAR-xcex4 receptor antagonists,
compounds of Formula I that act as PPAR-xcex3 receptor antagonists,
compounds of Formula I that act as both PPAR-xcex1 and PPAR-xcex3 receptor antagonists,
compounds of Formula I that act as both PPAR-xcex1 and PPAR-xcex4 receptor antagonists, and
compounds of Formula I that act as both PPAR-xcex3 and PPAR-xcex4 receptor antagonists.
An embodiment according to the invention is directed to treating a patient suffering from a physiological disorder capable of being modulated by a compound of Formula I having PPAR ligand binding activity, comprising administering to the patient a pharmaceutically effective amount of the compound, or a pharmaceutically acceptable salt thereof. Physiological disorders capable of being so modulated include, for example, cell differentiation to produce lipid accumulating cells, regulation of insulin sensitivity and blood glucose levels, which are involved in hypoglycemia/hyperinsulinism (resulting from, for example, abnormal pancreatic beta cell function, insulin secreting tumors and/or autoimmune hypoglycemia due to autoantibodies to insulin, autoantibodies to the insulin receptor, or autoantibodies that are stimulatory to pancreatic beta cells), macrophage differentiation which leads to the formation of atherosclerotic plaques, inflammatory response, carcinogenesis, hyperplasia, adipocyte gene expression, adipocyte differentiation, reduction in the pancreatic xcex2-cell mass, insulin secretion, tissue sensitivity to insulin, liposarcoma cell growth, chronic anovulation, hyperandrogenism, progesterone production, steroidogenesis, redox potential and oxidative stress in cells, nitric oxide synthase (NOS) production, increased gamma glutamyl transpeptidase, catalase, plasma triglycerides, HDL and LDL cholesterol levels and the like.
Another embodiment according to the invention is directed to a method of treating a disease state in a patient with a pharmaceutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the disease is associated with a physiological detrimental blood level of insulin, glucose, free fatty acids (FFA), or triclycerides.
An embodiment according to the invention is directed to treating a patient suffering from a physiological disorder associated with physiologically detrimental levels of triclycerides in the blood, by administering to the patient a pharmaceutically effective amount of the compound, or of a pharmaceutically acceptable salt thereof.
An embodiment according to the invention is the use of compounds of Formula I and their pharmaceutical compositions as anti-diabetic, anti-lipidemic, anti-hypertensive or anti-arteriosclerotic agents, or in the treatment of obesity.
Another embodiment according to the invention is directed to a method of treating hyperglycemia in a patient, by administering to the patient a pharmaceutically effective amount to lower blood glucose levels of a compound of Formula I, or a pharmaceutically acceptable salt thereof. Preferably, the form of hyperglycemia treated in accordance with this invention is Type II diabetes.
Another embodiment according to the invention is directed to a method of reducing triglyceride levels in a patient, comprising administering to the patient a therapeutically effective amount (to lower triglyceride levels) of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
Another embodiment according to the invention is directed to a method of treating hyperinsulinism in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
Another embodiment according to the invention is directed to a method of treating insulin resistance in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
Another embodiment according to the invention is directed to a method of treating cardiovascular disease, such as atherosclerosis in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
Another embodiment according to the invention is directed to treating of hyperlipidemia in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
Another embodiment according to the invention is directed to treating of hypertension in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
Another embodiment according to the invention is directed to treating eating disorders in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. Treatment of eating disorders includes the regulation of appetite andor food intake in patients suffering from under-eating disorders such as anorexia nervosa as well as over-eating disorders such as obesity and anorexia bulimia.
Another embodiment according to the invention is directed to treating a disease state associated with low levels of HDL comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. Diseases associated with low levels of HDL include atherosclerotic diseases.
Another embodiment according to the invention is directed to treating polycystic ovary syndrome comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
Another embodiment according to the invention is directed to treating climacteric comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
Another embodiment according to the invention is directed to treating inflammatory diseases such as rheumatoid arthritis, chronic obstructive pulmonary disease (emphysema or chronic bronchitis), or asthma comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
Another aspect of the invention is to provide a novel pharmaceutical composition which is effective, in and of itself, for utilization in a beneficial combination therapy because it includes a plurality of active ingredients which may be utilized in accordance with the invention.
In another aspect, the present invention provides a method for treating a disease state in a patient, wherein the disease is associated with a physiological detrimental level of insulin, glucose, free fatty acids (FFA), or triglycerides, in the blood, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, and also administering a therapeutically effective amount of an additional hypoglycemic agent.
In another aspect, the present invention provides a method for treating a disease state in a patient, wherein the disease is associated with a physiological detrimental level of insulin, glucose, free fatty acids (FFA), or triglycerides, in the blood, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, and also administering a therapeutically effective amount of a biguanidine compound.
In another aspect, the present invention provides a method for treating a disease state in a patient, wherein the disease is associated with a physiological detrimental level of insulin, glucose, free fatty acids (FFA), or triglycerides, in the blood, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, and also administering a therapeutically effective amount of metformin.
The invention also provides kits or single packages combining two or more active ingredients useful in treating the disease. A kit may provide (alone or in combination with a pharmaceutically acceptable diluent or carrier), a compound of Formula (I) and an additional hypoglycaemic agent (alone or in combination with diluent or carrier).
There are many known hypoglycemic agents in the art, for example, insulin; biguanidines, such as metformin and buformin; sulfonylureas, such as acetohexamide, chloropropamide, tolazamide, tolbutamide, glyburide, glypizide and glyclazide; thiazolidinediones, such as troglitazone; xcex1-glycosidase inhibitors, such as acarbose and miglatol; and B3 adrenoreceptor agonists such as CL-316,243.
Since sulfonylureas are known to be capable of stimulating insulin release, but are not capable of acting on insulin resistance, and compounds of Formula I are able to act on insulin resistance, it is envisaged that a combination of these medicaments could be used as a remedy for conditions associated with both deficiency in insulin secretion and insulin-resistance.
Therefore, the invention also provides a method of treating diabetes mellitus of type II in a patient comprising administering a compound of Formula I and one or more additional hypoglycemic agents selected from the group consisting of sulfonylureas, biguanidines, thiazolidinediones, B3-adrenoreceptor agonists, xcex1-glycosidase inhibitors and insulin.
The invention also provides a method of treating diabetes mellitus of type II in a patient comprising administering a compound of Formula I and a sulfonylurea selected from the group consisting of acetohexamide, chlorpropamide, tolazamide, tolbutamide, glyburide, glypizide and glyclazide.
The invention also provides a method of treating diabetes mellitus of type II in a patient comprising administering a compound of Formula I and a biguanidine selected from the group consisting of metformin and buformin.
The invention also provides a method of treating diabetes mellitus of type II in a patient comprising administering a compound of Formula I and an xcex1-glycosidase inhibitor selected from the group consisting acarbose and miglatol.
The invention also provides a method of treating diabetes mellitus of type II in a patient comprising administering a compound of Formula I and an thiazolidinedione, for example, troglitazone.
As indicated above, a compound of Formula I may be administered alone or in combination with one or more additional hypoglycemic agents. Combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound of Formula I and one or more additional hypoglycemic agent, as well as administration of the compound of Formula I and each additional hypoglycemic agents in its own separate pharmaceutical dosage formulation. For example, a compound of Formula I and hypoglycemic agent can be administered to the patient together in a single oral dosage composition such as a tablet or capsule, or each agent administered in separate oral dosage formulations. Where separate dosage formulations are used, the compound of Formula I and one or more additional hypoglycemic agents can be administered at essentially the same time, i.e., concurrently, or at separately staggered times, i.e., sequentially.
For example, the compound of Formula I may be administered in combination with one or more of the following additional hypoglycemic agents: insulin; biguanidines such as metformin or buformin; sulfonylureas such as acetohexamide, chloropropamide, tolazamide, tolbutamide, glyburide, glypizide or glyclazide; thiazolidinediones such as troglitazone; xcex1-glycosidase inhibitors such as acarbose or miglatol; or B3 adrenoreceptor agonists such as CL-316,243.
The compound of Formula I is preferably administered with a biguanidine, in particular, metformin.
The compounds of Formula I contain at least two aromatic or hetero-aromatic rings, which may be designated as shown in Formula II below, and for which their substitution pattern along the chain with respect to each other also is shown below. 
A preferred aspect of the compounds of Formula II, is a compound wherein 
is selected from quinolinyl, benzothiophenyl, benzoimidazolyl, quinazolinyl, benzothiazolyl, quinoxalinyl, naphthyl, pyridyl, 1H-indazolyl, 1,2,3,4-tetrahydroquinolinyl, benzofuranyl, thienyl, or indolyl, and one end of the linker, Linker I, is attached to 
preferably at the 2-position of the ring moiety.
Another aspect of the compounds of Formula II is a compound wherein 
is a 6-membered aryl or heteroaryl group and Linker I and Linker II are attached to 
at positions 1,3-, or 1,4- to each other.
Another aspect of the compounds of Formula II is a compound wherein 
is a naphthyl group, Linker I and Linker II are attached to 
at positions 1,4-, or 2,4- to each other on the naphthyl moiety.
A further preferred aspect of the compound of Formula II is described by Formula V below: 
where R7, R8, c, d, E and Z are as defined above, c+d=1-3, and Rxe2x80x2 and Rxe2x80x3 are ring system substituents.
Another aspect of this invention is a compound of the invention wherein 
is optionally substituted aryl, optionally substituted azaheteroaryl, or optionally substituted fused arylheterocyclenyl or fused arylheterocyclyl; and 
is optionally substituted phenyl or optionally substituted naphthyl, optionally substituted heteroaryl, or optionally substituted fused arylheterocyclenyl.
Another aspect of this invention is a compound of the invention wherein a=1 or 2; R1 and R2 is hydrogen; A is a chemical bond; and b=0.
Another aspect of this invention is a compound of the invention wherein a=0, 1, or 2, A is xe2x80x94C(O)N(R15)xe2x80x94 or xe2x80x94N(R14)C(O)xe2x80x94, and b=0 or 1.
Another more preferred aspect of this invention is a compound of the invention wherein R1 and R2 are both hydrogen, a=1, A is xe2x80x94Oxe2x80x94 and b=0.
Another more preferred aspect of this invention is a compound of the invention wherein R1 and R2 are both hydrogen, a=2, A is xe2x80x94Oxe2x80x94 and b=0.
Another more preferred aspect of this invention is a compound of the invention wherein a=0, A is xe2x80x94Oxe2x80x94 or xe2x80x94NR13xe2x80x94; R13 is hydrogen or alkyl; R3 and R4 are both independently hydrogen; and b=1.
Another aspect of this invention is a compound of the invention wherein a=0; A is 
R15 and R16 are hydrogen; g is 1, 2, 3 or 4; and b=0.
Another aspect of this invention is a compound of the invention wherein a=0; A is xe2x80x94NR13xe2x80x94, b=1, R3 and R4 are hydrogen, and R13 is hydrogen, alkyl, or R22(Oxe2x95x90)Cxe2x80x94.
Another aspect of this invention is a compound of the invention wherein a=2; then the vicinal R1 radicals taken together with the carbon atoms through which these radicals are linked form a 
group; R2 is hydrogen; A is a chemical bond or xe2x80x94Oxe2x80x94; and b=0.
Another aspect of this invention is a compound of the invention wherein a=6; then at least one pair of vicinal R1 radicals taken together with the carbon atoms through which these radicals are linked form a 
group; R2 is hydrogen or alkyl; A is xe2x80x94Oxe2x80x94; and b=0.
Another aspect of this invention is a compound of the invention wherein a=1, 2 or 3; R1 and R2 are hydrogen; A is xe2x80x94Oxe2x80x94; and b=0.
Another aspect of this invention is a compound of the invention wherein a=1; R1, R2, R3 and R4 are hydrogen; A is xe2x80x94Oxe2x80x94; and b=1.
Another aspect of this invention is a compound of the invention wherein a=2; A is 
h=1 or 2; and b=0.
Another aspect of this invention is a compound of the invention wherein c=0; d=0; B and E is a chemical bond; Z is R21O2SHNCOxe2x80x94, and R21 is phenyl.
Another aspect of this invention is a compound of the invention wherein c=0; d=2; B is xe2x80x94C(O)N(R20)xe2x80x94, E is a chemical bond; Z is a tetrazolyl group or xe2x80x94CO2R21; R20 is hydrogen, alkyl, alkoxycarbonyl.
Another aspect of this invention is a compound of the invention wherein c=0 or 4; d=0 or 1; B and E is a chemical bond; Z is tetrazolyl, NH2COxe2x80x94 or xe2x80x94CO2R21; and R21 is hydrogen or lower alkyl.
Another aspect of this invention is a compound of the invention wherein c=0 or 1; d=0 or 1; B is xe2x80x94Oxe2x80x94 or a chemical bond; E is a chemical bond; and Z is tetrazolyl, NH2COxe2x80x94 or xe2x80x94CO2R21; and R21 is hydrogen or lower alkyl.
Another aspect of this invention is a compound of the invention wherein c=0; d=1; B is xe2x80x94Oxe2x80x94 or a chemical bond; E is a chemical bond; R7 and R8 are hydrogen or alkyl; and Z is tetrazolyl, NH2COxe2x80x94 or xe2x80x94CO2R21; and R21 is hydrogen or lower alkyl.
Another aspect of this invention is a compound of the invention wherein c=2 or 4, then at least one pair of vicinal R5 radicals taken together with the carbon atoms to which the R5 radicals are linked form a 
group; d=0; D and E is a chemical bond; and Z is a tetrazolyl group or xe2x80x94CO2R21; and R21 is hydrogen.
Another aspect of this invention is a compound of the invention wherein c=0; d=3 or 4; B is xe2x80x94Oxe2x80x94; E is a chemical bond; R7 and R8 are hydrogen or alkyl, or at least one of R7 is carboxyl or alkoxycarbonyl; Z is tetrazolyl, xe2x80x94CO2R21 or (R21)2NC(O)xe2x80x94; and R21 is hydrogen or lower alkyl.
Another aspect of this invention is a compound of the invention wherein c=0; d=1, 2, or 3; B is xe2x80x94C(O)xe2x80x94; E is a chemical bond; R7 and R8 are hydrogen or alkyl; Z is tetrazolyl or xe2x80x94CO2R21; and R21 is hydrogen or lower alkyl.
Another aspect of this invention is a compound of the invention wherein c=4; d=0; B and E are a chemical bond; R7 and R8 are hydrogen or alkyl; Z is tetrazolyl or xe2x80x94CO2R21; and R21 is hydrogen or lower alkyl.
Another aspect of this invention is a compound of the invention wherein c=0, 1 or 2; d=1, 2 or 3; B is xe2x80x94Sxe2x80x94 or NR19, E are a chemical bond; R5, R6, R7 and R8 are hydrogen; Z is tetrazoly or xe2x80x94CO2R21; and R21 is hydrogen or lower alkyl.
Another aspect of this invention is a compound of the invention wherein R6 and R8 are xe2x80x94(CH2)qxe2x80x94X; q is 0, 1 or 2; and X is independently hydrogen, aralkyl or lower alkyl.
Another aspect of this invention is a compound of the invention wherein at least one pair of geminal R5 and R6 radicals taken together with the carbon atom through which these radicals are linked form a 5-membered cycloalkyl group.
Another aspect of this invention is a compound of the invention wherein at least one pair of geminal R7 and R8 radicals taken together with the carbon atom through which these radicals are linked form a 5-membered cycloalkyl group.
Another aspect of this invention is a compound of the invention wherein Z is xe2x80x94CO2H, xe2x80x94CN or a tetrazolyl group.
A preferred aspect of this invention is a compound of the invention wherein 
is an optionally substituted quinolinyl, quinoxalinyl, quinazolinyl, isoquinolinyl, N-alkyl-quinolin-4-onyl, quinazolin-4-onyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, benzothiophenyl, indolinyl oxazolyl, thiazolyl, oxadiazolyl isoxazolyl, imidazolyl, pyrazol-yl, thiadiazolyl, triazolyl, pyridyl pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, or napthalenyl group, wherein the substituent is a ring system substituent as defined herein, more preferably a substituent selected from the group consisting of phenyl, substituted-phenyl, thienyl, substituted thienyl, cycloalkyl, lower alkyl, branched alkyl, fluoro, chloro, alkoxy, aralkyloxy, trifluoromethyl and trifluoromethyloxy.
A more preferred aspect of this invention is a compound of the invention wherein 
is unsubstituted quinolin-2-yl, 3-substituted quinolin-2-yl, 4-substituted quinolin-2-yl, 6-substituted quinolin-2-yl or 7 substituted quinolin-2-yl; an unsubstituted quinozalin-2-yl, 3-substituted quinozalin-2-yl, 6-substituted quinozalin-2-yl or 3,6-disubstituted quinozalin-2-yl; unsubstituted quinazolin-2-yl, 4-substituted quinazolin-2-yl or 6-substituted quinazolin-2-yl; unsubstituted isoquinolin-3-yl, 6-substituted isoquinolin-3-yl or 7-substituted isoquinolin-3-yl; 3-substituted-quinazolin-4-on-2-yl; N-substituted quinolin-4-on-2-yl; 2-substituted-oxazol-4-yl or 2,5 disubstituted-oxazol-4-yl; 4-substituted oxazol-2-yl or 4,5-disubstituted-oxazol-2-yl; 2-substituted thiazol-4-yl or 2,5-disubstituted thiazol-4-yl; 4-substituted thiazol-2-yl or 4,5-disubstituted-thiazol-2-yl; 5-substituted-[1,2,4]oxadiazol-3-yl; 3-substituted-[1,2,4]oxadiazol-5-yl; 5-substituted-imidazol-2-yl or 3,5-disubstituted-imidazol-2-yl; 2-substituted-imidazol-5-yl or 2,3-disubstituted-imidazol-5-yl; 3-substituted-isoxazol-5-yl; 5-substituted-isoxazol-3-yl; 5-substituted-[1,2,4]thiadiazol-3-yl; 3-substituted-[1,2,4]-thiadiazol-5-yl; 2-substituted-[1,3,4]-thiadiazol-5-yl; 2-substituted-[1,3,4]-oxadiazol-5-yl; 1-substituted-pyrazol-3-yl; 3-substituted-pyrazol-5-yl; 3-substituted-[1,2,4]-triazol-5-yl; 1-substituted-[1,2,4]-triazol-3-yl; 3-substituted pyridin-2-yl, 5-substituted pyridin-2-yl, 6-substituted pyridin-2-yl or 3,5-disubstituted pyridin-2-yl; 3-substituted pyrazin-2-yl, 5-substituted pyrazin-2-yl, 6-substituted pyrazin-2-yl or 3,5 disubstituted-pyrazin-2-yl; 5-substituted pyrimidin-2-yl or 6-substituted-pyrimidin-2-yl; 6-substituted-pyridazin-3-yl or 4,6-disubstituted-pyridazin-3-yl; unsubstituted napthalen-2-yl, 3-substituted napthalen-2-yl, 4-substituted napthalen-2-yl, 6-substituted napthalen-2-yl or 7 substituted napthalen-2-yl; 2-substituted phenyl, 4-substituted phenyl or 2,4-disubstituted phenyl; unsubstituted-benzothiazol-2-yl or 5-substituted-benzothiazol-2-yl; unsubstituted benzoxazol-2yl or 5-substituted-benzoxazol-2yl; unsubstituted-benzimidazol-2-yl or 5-substituted-benzimidazol-2-yl; unsubstituted-thiophen-2yl, 3-substituted-thiophen-2yl, 6-substituted-thiophen-2yl or 3,6-disubstituted-thiophen-2yl; unsubstituted-benzofuran-2-y, 3-substituted-benzofuran-2-yl, 6-substituted-benzofuran-2-yl or 3,6-disubstituted-benzofuran-2-yl; 3-substituted-benzofuran-6-yl or 3,7-disubstituted-benzofuran-6-yl, wherein the substituent is a ring system substituent as defined herein, more preferably a substituent selected from the group consisting of phenyl, substituted-phenyl, thienyl, substituted thienyl, cycloalkyl, lower alkyl, branched alkyl, fluoro, chloro, alkoxy, aralkyloxy, trifluoromethyl and trifluoromethyloxy.
Another more preferred aspect of this invention is a compound of the invention wherein a=0, A is xe2x80x94Oxe2x80x94 or xe2x80x94NR13xe2x80x94; R13 is hydrogen or alkyl; R3 and R4 are both independently hydrogen; b=1; and ArI is 3-substituted quinolin-2-yl, 4-substituted quinolin-2-yl, 6-substituted quinolin-2-yl, 7 substituted quinolin-2-yl, unsubstituted quinoxalin-2-yl, 3-substituted quinoxalin-2-yl, 6-substituted quinoxalin-2-yl, 3,6-disubstituted quinoxalin-2-yl, unsubstituted quinazolin-2-yl, 4-substituted quinazolin-2-yl, 6-substituted quinazolin-2-yl, unsubstituted isoquinolin-3-yl, 6-substituted isoquinolin-3-yl, 7-substituted isoquinolin-3-yl, 4-substituted oxazol-2-yl, 4,5-disubstituted-oxazol-2-yl, 4-substituted-thiazol-2-yl, 4,5-disubstituted-thiazol-2-yl, 5-substituted-imidazol-2-yl, 3,5-disubstituted-imidazol-2-yl, 1-substituted-pyrazol-3-yl, 3-substituted-pyrazol-5-yl, 3-substituted pyridin-2-yl, 5-substituted pyridin-2-yl, 6-substituted pyridin-2-yl or 3,5-disubstituted pyridin-2-yl, 3-substituted pyrazin-2-yl, 5-substituted pyrazin-2-yl, 6-substituted pyrazin-2-yl, 3,5 disubstituted-pyrazin-2-yl, 5-substituted pyrimidin-2-yl, 6-substituted-pyrimidin-2-yl, 6-substituted-pyridazin-3-yl, 4,6-disubstituted-pyridazin-3-yl, unsubstituted-benzothiazol-2-yl, 5-substituted-benzothiazol-2-yl, unsubstituted-benzoxazol-2-yl, 5-substituted-benzoxazol-2-yl, unsubstituted benzimidazol-2-yl, 5-substituted-benzimidazol-2-yl, 3-substituted-benzofuran-6-yl or 3,7-disubstituted-benzofuran-6-yl.
Another aspect of this invention is a compound of formula I as described by formula (Ia) below: 
wherein 
is independently aryl, fused arylcycloalkenyl, fused arylcycloalkyl, fused arylheterocyclenyl, fused arylheterocyclyl, heteroaryl, fused heteroarylcycloalkenyl, fused heteroarylcycloalkyl, fused heteroarylheterocyclenyl, or fused heteroarylheterocyclyl;
a=1;
b=0;
R1 and R2 are hydrogen
A is xe2x80x94Oxe2x80x94;
R5, R6, R7, R8 are hydrogen;
c=0;
B and E are a chemical bond;
Z is R21O2Cxe2x80x94, R21OCxe2x80x94, cyclo-imide, xe2x80x94CN, R21O2SHNCOxe2x80x94, R21O2SHNxe2x80x94, (R21)2NCOxe2x80x94, R21Oxe2x80x942,4-thiazolidinedionyl, or tetrazolyl;
Rxe2x80x2 and Rxe2x80x3 are ring system substituents as defined herein, more preferably, Rxe2x80x2 is hydrogen, lower alkyl, halo, alkoxy, aryloxy or aralkyloxy; and Rxe2x80x3 is lower alkyl, hydrogen, aralkyloxy, alkoxy, cycloalkylalkyloxy or halo.
Another aspect of this invention is a compound of formula I as described by formula (Ia) wherein 
is independently aryl, fused arylcycloalkenyl, fused arylcycloalkyl, fused arylheterocyclenyl, fused arylheterocyclyl, heteroaryl, fused heteroarylcycloalkenyl, fused heteroarylcycloalkyl, fused heteroarylheterocyclenyl, or fused heteroarylheterocyclyl;
a=1; 
g=2, 3, 4 or 5;
R1, R2, R3, R4, R15 and R16 are hydrogen;
b=0 or 1;
c=0;
d=0;
B and E are a chemical bond;
Z is xe2x80x94CO2H;
Rxe2x80x2 and Rxe2x80x3 are ring system substituents as defined herein, more preferably, Rxe2x80x2 is hydrogen, lower alkyl, halo, alkoxy, aryloxy or aralkyloxy; and Rxe2x80x3 is lower alkyl, alkoxy, aralkoxy, cycloalkylalkoxy or halo.
Another aspect of this invention is a compound of formula I as described by formula (Ia) wherein 
is independently aryl, fused arylcycloalkenyl, fused arylcycloalkyl, fused arylheterocyclenyl, fused arylheterocyclyl, heteroaryl, fused heteroarylcycloalkenyl, fused heteroarylcycloalkyl, fused heteroarylheterocyclenyl, or fused heteroarylheterocyclyl;
a=1; 
g=2, 3, 4 or 5;
R1, R2, R3, R4, R15 and R16 are hydrogen;
b=0 or 1;
c=0;
d=0;
B and E are a chemical bond;
Z is xe2x80x94CO2H;
Rxe2x80x2 is hydrogen; and Rxe2x80x3 is lower alkyl.
Another aspect of this invention is a compound of formula I as described by formula (Ia) wherein 
is independently aryl, fused arylcycloalkenyl, fused arylcycloalkyl, fused arylheterocyclenyl, fused arylheterocyclyl, heteroaryl, fused heteroarylcycloalkenyl, fused heteroarylcycloalkyl, fused heteroarylheterocyclenyl, or fused heteroarylheterocyclyl;
a=1; 
g=2, 3, 4 or 5;
R1, R2, R3, R4, R15 and R16 are hydrogen;
R7 and R8 are independently hydrogen;
b=0 or 1;
c=0;
d=1;
B and E are a chemical bond;
Z is xe2x80x94CO2H;
Rxe2x80x2 and Rxe2x80x3 are ring system substituents as defined herein, more preferably, Rxe2x80x2 is hydrogen, lower alkyl, halo, alkoxy, aryloxy or aralkyloxy; and Rxe2x80x3 is lower alkyl, alkoxy, aralkoxy, cycloalkylalkoxy or halo.
Another aspect of this invention is a compound of formula I as described by formula (Ia) wherein 
is independently aryl, fused arylcycloalkenyl, fused arylcycloalkyl, fused arylheterocyclenyl, fused arylheterocyclyl, heteroaryl, fused heteroarylcycloalkenyl, fused heteroarylcycloalkyl, fused heteroarylheterocyclenyl, or fused heteroarylheterocyclyl;
a=1; 
g=2, 3, 4 or 5;
R1, R2, R3, R4, R15 and R16 are independently hydrogen;
R7 and R8 are hydrogen
b=0 or 1;
c=0;
d=1;
B and E are a chemical bond;
Z is xe2x80x94CO2H;
Rxe2x80x2 is hydrogen; and Rxe2x80x3 is lower alkyl.
Another aspect of this invention is a compound of formula I as described by formula (Ia) wherein:
a=0-2;
b=0-1;
A is xe2x80x94Oxe2x80x94 or xe2x80x94NR13xe2x80x94;
R1, R2, R3 and R4 are independently hydrogen;
R13 is hydrogen, R22OCxe2x80x94, or alkyl;
c=0;
d=0;
B and E are a chemical bond;
Z is xe2x80x94CO2H;
Rxe2x80x2 and Rxe2x80x3 are ring system substituents as defined herein, more preferably, Rxe2x80x2 is lower alkyl, halo, alkoxy, aryloxy or aralkyl; and Rxe2x80x3 is lower alkyl or halo.
A more preferred aspect of this invention is a compound of formula I as described by formula (Ia) wherein:
a 1 or 2;
A is xe2x80x94Oxe2x80x94;
b=0;
R1, R2, R7 and R8 are independently hydrogen;
c=0;
d=1;
B and E are a chemical bond;
Rxe2x80x2 is hydrogen, halo or benzyloxy;
Rxe2x80x3 is lower alkyl, preferably methyl;
Z is xe2x80x94CO2H.
A more preferred aspect of this invention is a compound of formula I as described by formula (Ia) wherein:
a=1 or 2;
A is xe2x80x94Oxe2x80x94;
b=0;
R1, R2, R7 and R8 are independently hydrogen;
c=0;
d=1;
B and E are a chemical bond;
Rxe2x80x2 is hydrogen, halo or benzyloxy;
Rxe2x80x3 is lower alkyl, preferably methyl;
Z is xe2x80x94CO2H.
A more preferred aspect of this invention is a compound of formula I as described by formula (Ia) wherein:
a=1 or 2;
A is xe2x80x94Oxe2x80x94;
b=0;
R1, R2, R7, R8 are independently hydrogen;
c=0;
B is xe2x80x94Oxe2x80x94;
d=1;
B and E are a chemical bond;
Rxe2x80x2 is halo;
Rxe2x80x3 is lower alkyl, preferably methyl;
Z is xe2x80x94CO2H.
A more preferred aspect of this invention is a compound of formula I as described by formula (Ia) wherein:
a=1;
R1 and R2 are hydrogen
A is xe2x80x94Oxe2x80x94;
b=0;
c=0;
d=0;
B and E are a chemical bond;
Rxe2x80x2 is hydrogen, aralkoxy, or halo;
Rxe2x80x3 is lower alkyl, preferably methyl;
Z is xe2x80x94CO2H.
A more preferred aspect of this invention is a compound of formula I as described by formula (Ia) wherein:
a=1;
A is xe2x80x94Oxe2x80x94;
b=0;
c=0;
d=0;
B and E are a chemical bond;
Rxe2x80x2 is hydrogen;
Rxe2x80x3 is lower alkyl;
Z is xe2x80x94CO2H.
A more preferred aspect of this invention is a compound of formula I as described by formula (Ia) wherein: 
is aryl or heteroaryl;
a=1;
A is xe2x80x94Oxe2x80x94;
b=0;
c=0;
d=0;
B and E are a chemical bond;
Rxe2x80x2 is hydrogen;
Rxe2x80x3 is lower alkyl;
Z is xe2x80x94CO2H.
A more preferred aspect of this invention is a compound of formula I as described by formula (Ia) wherein: 
is optionally substituted azaheteroaryl;
a=1;
A is xe2x80x94Oxe2x80x94;
b=0;
c=0;
d=0;
B and E are a chemical bond;
Rxe2x80x2 is hydrogen;
Rxe2x80x3 is lower alkyl;
Z is CO2H.
A more preferred aspect of this invention is a compound of formula I as described by formula (Ia) wherein: 
is optionally substituted quinolinyl, or a 5-membered heteroaryl group wherein the heteroaryl group is substituted by optionally substituted phenyl or optionally substituted cyclohexyl;
a=1;
A is xe2x80x94Oxe2x80x94;
b=0;
c=0;
d=0;
B and E are a chemical bond;
Rxe2x80x2 is hydrogen;
Rxe2x80x3 is lower alkyl;
Z is CO2H.
A preferred compound according to the invention is selected from the group consisting of 
A preferred compound according to the invention is selected from the group consisting of 
A preferred compound, selective for PPARxcex3, is chosen from the group consisting: 
A preferred compound, selective for PPARxcex1, is chosen from the group consisting: 
A preferred compound having PPARxcex1 and PPARxcex3 activity is selected from the group consisting: 
A preferred compound having PPARxcex1 and PPARxcex4 activity is selected from the group consisting: 
This invention also encompasses all combinations of preferred aspects of the invention described herein.
Compounds useful according to this invention can be prepared by the methods disclosed herein as well as the specific examples and in the following references which are incorporated herein by reference: Galemmo, Robert A., Jr et. al, J. Med. Chem. (1990), 33(10), 2828-41; Youssefyeh, Raymond D. et al, J. Med. Chem. (1990), 33(4), 1186-94; Youssefyeh, Raymond et. al, International patent publication no. WO 8705510; Astles, Peter Charles et. al., International patent publication no. WO 9513262, Jayossi et al, International patent application Ser. No. PCT/US00/11490 in the name of Aventis Pharmeuticals Products Inc, filed on Apr. 28th 2000; and Jayossi et al, U.S. non-provisional patent application titled xe2x80x9cTherapeutic uses of Tri-Aryl Acid Derivativesxe2x80x9d in the name of Jayossi et al., Ser. No. 50/131,454 filed on Apr. 28th 1999, incorporated herein in their entirety.
Compounds useful according to this invention can be prepared in segments, as is common to a long chain molecule. Thus, it is convenient to synthesize these molecules by employing condensation reactions at the A and B sites of the molecule. Compounds of Formula I can be prepared by the application or adaptation of known methods, by which is meant methods used heretofore or described in the literature. For example, the synthetic methodology described in the following publications, the contents of which are incorporated herein by reference may be employed: xe2x80x9cDevelopment of a novel series of (2-quinolinylmethoxy)phenyl-containing compounds as high-affinity leukotriene receptor antagonists. 1. Initial structure-activity relationships.xe2x80x9d J. Med. Chem. (1990), 33(4), 1186-1194; xe2x80x9cThe development of a novel series of (quinolin-2-ylmethoxy)phenyl-containing compounds as high-affinity leukotriene receptor antagonists. 3. Structural variation of the acidic side chain to give antagonists of enhanced potency.xe2x80x9d J. Med. Chem. (1990), 33(10), 2828-41; xe2x80x9cA Novel Series of [2-(Methylphenethylamino)-2-oxoethyl]benzene-Containing Leukotriene B4 Antagonists: Initial Structure-Activity Relationships.xe2x80x9d J. Med. Chem. (1996), 39(19), 3748-3755; and xe2x80x98Structure-Activity Relationships Study of Two Series of Leukotriene B4 Antagonists: Novel Indolyl and Naphthyl Compounds Substituted with a 2-[Methyl(2-phenethyl)amino]-2-oxoethyl Side Chain.xe2x80x9d J. Med. Chem. (1996), 39(19), 3756-3768.
Additional methodologies which can be used to synthesize construct compounds of this invention are described below. The coupling of an aryl-halide with a terminal alkyne using a Pd(0) catalyst (the Sonikashira coupling) or a variant thereof can be used to assemble molecules as described in Scheme 100.
Partial reduction using mild hydrogenation conditions, for example with a catalyst poison such as quinoline, can provide the cis olefin. Isomerization of the olefin can be accomplished, if desired, to provide the trans olefin. Either of these olefins can be used as intermediates for further elaboration. They also are compounds which, themselves, can act as PPAR modulators.
Reduction of the olefin can be accomplished by hydrogenation, for example H2, Pd/C. 
A modification of this chemistry is shown in Scheme 101 below. Coupling of the aryl halide and terminal alkyne provides an intermediate which can be subsequently reduced as above and then coupled with an intermediate having a leaving group L as described in earlier sections. Alternatively, each alkyne or alkene intermediate can be coupled with a fragment which contains a leaving group L to provide the corresponding alkynyl and alkenyl analogs. 
Additional chemistry which can be employed is shown in Scheme 102. Heteroaromatic systems which have an acidic Cxe2x80x94H bond can be deprotonated with a base such as BuLi or a grignard reagent, and the resulting anion can be reacted with an electrophile such as an aldehyde, ketone, carboxylic acid derivative, epoxide, etc. as shown. 
A further elaboration of this chemistry is shown in scheme 103, wherein a heteroaromatic ring is deprotonated with a base such as BuLi and the anion is condensed with an aldehyde. The resulting alcohol can be deoxygenated using conditions such as Barton""s tin hydride mediated reduction of a thiono carbamate or zanthate or by using conditions for the reduction of benzylic alcohols such as Et3SiH, TFA. A representative example of the condensation product is shown. 
In another embodiment of this invention Ar I or Ar II is defined as a benzofuran. This type of ring system can be assembled in various ways using literature methods (for examples, see Friedlichsen, W. in Comprehensive Heterocyclic Chemstry II, Vol 2. Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V. Eds. Elsevier Science 1996). A particularly suitable method with regard to this invention involves formation of a 2-methoxycarbonyl substituted benzofuran from a bromo substituted-ortho-hydroxy benzaldehyde, (Foster, R. T.; Robertson, A.; Bushra, A.; J. Chem Soc., 1948, 2254) as illustrated in scheme 104. Ring closure is carried out in the presence of base such as sodium methoxide in methanol or lithium hexamethyldisilazide in a solvent such as THF, DME, DMPU or a mixture thereof, generally at a temperature between xe2x88x9278xc2x0 C. and reflux. The resulting 2-methoxycarbonyl benzofuran can then be further derivatized, as illustrated in scheme 104 or as described elsewhere in this experimental section, to provide a variety of appositely substituted benzofurans. 
In one particular embodiment of this invention, AR I or Ar II is defined as a heterocycle such as pyridine, pyrimidine and pyridazine. In principle, appropriately functionalized ring systems of this kind can be prepared by functionalization of specific precursors followed by ring synthesis or by derivatization of a preformed ring system. There are numerous approaches to the synthesis and functionalization of the aforementioned heterocyclic frameworks in the chemical literature (for examples, see (a) Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V. Eds. Comprehensive Heterocyclic Chemstry II, Vol 5 and Vol 6. Elsevier Science 1996 and references therein). A particularly useful protocol with regard to the current invention involves Mitsunobu etherification of hydroxyl substituted heterocycles such as outlined in Scheme A. Treatment of 5-bromo-pyridin-2-one (1, G, Jxe2x95x90CH), 5-bromo-pyrimidin-2-one (2, Gxe2x95x90N, Jxe2x95x90CH) or bromo-pyrazin-3-one (3, Gxe2x95x90CH, Jxe2x95x90N) with an alcohol under Mitsunobu""s conditions provides the corresponding bromo-substituted heterocyclic ethers (4) (for typical procedures see Mitsunobu. O., Synthesis, 1981, 1). 
These heterocyclic bromides can be further functionalized in a number of ways. For example, coupling with a vinyl stannane can be effected under palladium(0) catalysis to provide systems with an alkenyl side chain (5 and 6). The choice of catalyst and reaction temperature depends on the substrate employed but is most commonly tetrakistriphenylphosphine palladium, bis(triphenylphosphine)palladium chloride, 1,1xe2x80x2-bis(diphenylphosphino)ferrocene/bis-dibenzylideneacetone palladium or 1,2 bis-(diphenylphosphino)ethane/bis(acetonitrile)dichloropalladium at a temperature between 50 and 150xc2x0 C. Suitable solvents include DMF, DMPU, HMPA, DMSO, toluene, and DME. (for examples see Farina, V. Krishnamurthy, V.; Scott, W. J. Organic Reactions, 1997, 50, 1). Reduction of the olefin using, for example Wilkinson""s catalyst in a solvent such as toluene, THF or an alcohol at a temperature between about 20 and 80xc2x0 C. provides the corresponding alkane (7). Heterocyclic bromides such as (1) can also be metalated (after protection of the carbonyl functionality as a O-silyl ether by reaction with an appropriate silyl chloride or triflate in the presence of a base such as triethylamine or imidazole in a solvent such as dichloromethane or DMF) with an alkyl lithium reagent generally at low temperature (below xe2x88x9250xc2x0 C.) Suitable solvents for this process include THF or diethyl ether, either alone or as mixtures with additives such as HMPA, TMEDA or DABCO. The resulting aryl lithium species can then be reacted with a variety of electrophiles such as aldehydes, alkyl halides, oxiranes, aziridines or ab-unaturated carbonyls to provide heterocycles substituted with a variety of functionalized side chains. In particular, by using DMF as the electrophile, this procedure can be used to install an aldehyde functional group on the heterocycle (8). The aldehyde can then be further functionalized by Wittig or Horner Emons reaction to produce olefin substituted heterocyclic silyl ethers (9). (For examples see Cadogan, J. I. G. Organophosphorus Reagents in Organic Synthesis, Academic Press, 1979 and references therein). The silyl ether can be cleaved using tetrabutyl ammonium fluoride in THF at room temperature or above (For examples see Protective Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts; John Wiley Publications 1998 and references therein). The resulting hydroxyl functionality can be converted to the corresponding triflate using N-phenyl triflimide and a base such as sodium hydride or sodium hexamethyldisilazide in a solvent such as THF or DME at or below room temperature. Coupling of the resulting triflate with a vinyl (or alkynyl ) stannane in the presence of lithium chloride and a Pd(0) catalyst as described above produces the corresponding bisalkenyl substituted heterocycles (10).
Bromo substituted heterocycles such as (11 and 12 scheme B) can be converted into the analogous hydroxyl substituted system by first, conversion to the borate ester (13) then oxidative cleavage of the carbon boron bond with an oxidant such as aqueous hydrogen peroxide in the presence of acid or base (such as acetic acid, sodium carbonate or sodium hydroxide) or oxone in the presence of a base (such as sodium carbonate) at or above 0xc2x0 C. (For examples see Webb, K. S.; Levy, D. Tetrahedron Letts., 1995, 36, 5117. and Koster, R.; Morita, Y. Angew. Chem., 1966, 78, 589). 
The resulting hydroxy substituted heterocycles (14) can be further derivatized as already described above to give ether (15) or alkenyl (16) substituted side chains. Certain heterocyclic bromides or chlorides situated ortho or para to a ring nitrogen can be readily displaced with an alcohol in the presence of base such as sodium hydride in a solvent such as Toluene, DMSO, THF, DMPU or HMPA at or above room temperature (For examples see Kelly, T. R. et al. J. Amer. Chem. Soc., 1994, 116, 3657 and Newkome, G. R. et al. J. Org. Chem., 1977, 42, 1500). In particular, alcoholysis of a 2,6-dibromo-pyridine using a controlled stoichiometric amount of alcohol reagent provides the alkoxy substituted-bromo-pyridine. Subsequent reaction of this product with a further equivalent of another alcohol provides the unsymmetrically dialkoxy-substituted heterocycle. 
Similar procedures using 2,4-dichloro-pyrimidine or 2,6-dibromo-pyridazine provides the corresponding dialkoxy-substituted pyrimidines and pyridazines. A simple alkoxy group positioned ortho to a nitrogen in these heterocyclic systems can be hydrolyzed to the corresponding hydroxy substituent using aqueous hydrochloric acid normally at or above room temperature (Scheme D). 
For example, treatment of the 2-methoxy-6-alkenyl-substituted pyridine (17) with hydrochloric acid provides the 6-alkenyl substituted pyridin-2-one. This intermediate, in turn, can be further derivatized to the corresponding 2-alkoxy (18) or 2-alkyl (19) substituted systems as previously described. A methyl, methylene or methine group positioned ortho to a ring nitrogen in these heterocyclic systems can be deprotonated with a base such as an alkyl lithium or LDA in a solvent such as THF ether or LIMPA, generally at low temperature (below 0xc2x0 C.) and the resulting anion reacted with electrophiles such as aldehydes epoxides alkyl halides or a,b-unsaturated carbonyl compounds to provide a variety of functionalized side chain substituents. 
For example (Scheme E), 2-alkoxy-4-methyl-pyrimidine (20) is treated with LDA at xe2x88x9278xc2x0 C. followed by an aldehyde to give the corresponding hydroxy adduct. Subsequent dehydration with trifluoroacetic acid in a solvent such as dichloromethane followed by hydrogenation of the resulting olefin provides the 4-alkyl-2-alkoxy-pyrimidine (21).
As illustrated above, compounds of Formula I can be prepared by art recognized procedures from known compounds or readily preparable intermediates. Thus, in order to prepare a compound of the formula: 
the following reactions or combinations of reactions can be employed: 
wherein:
R1, R2, R3, R4, R5, R6, R7, R8, a, b, c, d, A, and B are as defined above; E is a chemical bond; Z is xe2x80x94CN, xe2x80x94COOR3 or tetrazol, and L is a leaving group, such as halo, tosylate, or mesylate. Where A or B is O or S, any base normally employed to deprotonate an alcohol or thiol may be used, such as sodium hydride, sodium hydroxide, triethylamine, sodium bicarbonate or diisopropylethylamine.
Reaction temperatures are in the range of about room temperature to reflux, and reaction times vary from about 2 to about 96 hours. The reactions are usually carried out in a solvent that will dissolve both reactants and is inert to both as well. Suitable solvents include, but are not limited to, diethyl ether, tetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide, dioxane and the like.
In the case where B is SO or SO2 treatment of the thio compound with m-chlorobenzoic acid or sodium periodate results in the sulfinyl compound. Preparation of the sulfonyl compound may be accomplished by known procedures such as dissolving the sulfinyl compound in acetic acid and treating with 30% H2O2.
Those compounds where B is xe2x80x94C(xe2x95x90O)xe2x80x94 may be prepared by the following reaction sequence: 
Condensation of the aldehyde with 1,3-propanedithiol results in the dithiane compound. This may be carried out in chloroform at reduced temperatures of about xe2x88x9220xc2x0 C., while bubbling HCl gas into the reaction mixture. The dithiane compound is then treated with N-butyl lithium in nonpolar solvent at about xe2x88x9278xc2x0 C. and then reacted with the substituted benzyl chloride. This results in addition of Ring III to the molecule. The dithiane moiety is then treated with a mercuric chloride-mercuric oxide mixture to form the complex which is then split off leaving the desired compound.
Those compounds where A is a chemical bond may be prepared by known coupling methods, for example, the reaction of an appropriate alkyl halide with an appropriate organometallic reagent such as a lithium organocopper reagent (See Posner, Org. React. 22, 235-400 (1975), Normant, Synthesis 63-80 (1972), Posner, xe2x80x9cAn introduction to Synthesis Using Organocopper Reagentsxe2x80x9d p. 68-81, Wiley, New York, 1980); coupling of an appropriate lithium organocopper reagent, or Grignard reagent, with a suitable ester of sulfuric or sulfonic acid (see xe2x80x9cAn introduction to Synthesis Using Organocopper Reagentsxe2x80x9d p. 68-81, Wiley, New York, 1980, Kharasch and Reinmuth xe2x80x9cGrignard Reactions of Non Metallic Substancesxe2x80x9d, pp1277-1286, Prentice-Hall, Englewood Cliffs, N.J., 1954); or other known reactions for forming alkyl bonds (See March xe2x80x9cAdvanced Organic Chemistryxe2x80x9d p. 1149, Third Edition, Wiley, NY, 1985). 
where Xxe2x80x2 is halide, an ester of a sulfuric acid, or a sulfonic acid ester, and Yxe2x80x2 is a lithium organocopper reagent or a Grignard reagent.
There is no particular restriction on the nature of the reagent or solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved.
Alternatively, compounds where A is a chemical bond may be prepared by reduction of appropriate compounds, wherein A is an ethylene moiety, with a suitable reducing agent, for example H2/Pd/C.
There is no particular restriction on the solvent or nature of the reducing agent to be used in this reaction, and any solvent and reducing agent conventionally used in reactions of this type may equally be used here, provided that it has no adverse effect on other parts of the molecule. An example of a suitable reducing agent is H2/Pd/C. Other reducing reagents are known in the art. For example, see: Mitsui and Kasahara, in Zabicky, xe2x80x9cThe Chemistry of Alkenesxe2x80x9d, vol. 2, pp. 175-214, Interscience, NY, 1970; and Rylander xe2x80x9cCatalytic Hydrogenation over Platinum Metals,xe2x80x9d pp. 59-120, Academic Press, NY, 1967.
Those compounds wherein E is an ethylene moiety are prepared by reacting the appropriate aldehyde or ketone with a substituted Wittig reagent of the formula 
Condensation results in formation of the double bond. The Wittig reagent is prepared by known art recognized procedure, such as reaction of triphenyl phosphine or diethylphosphone with a suitable substituted alkyl/aryl bromide followed by treatment with a strong organometallic base such as n-BuLi or NaOH, resulting in the desired ylide. Conventional Wittig reaction conditions may be used in accordance with standard practice, for examples see Bestmann and Vostrowsky, Top. Curr. Chem. 109, 85-164 (1983), and Pommer and Thieme, Top. Curr. Chem. 109, 165-188 (1983).
There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved.
Of course this Wittig condensation may also take place when the Wittig reagent is formed on Ring II position of the molecule, which is then condensed with an aldehyde.
There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved.
There is no particular restriction on the solvent or nature of the reducing agent to be used in this reaction, and any solvent and reducing agent conventionally used in reactions of this type may equally be used here, provided that it has no adverse effect on other parts of the molecule. An Example of a suitable reducing agent is H2/Pd/C. Other reducing reagents are known in the art. For example, see: Mitsui and Kasahara, in Zabicky, xe2x80x9cThe Chemistry of Alkenesxe2x80x9d, vol. 2, p. 175-214, Interscience, NY, 1970; and Rylander xe2x80x9cCatalytic Hydrogenation over Platinum Metalsxe2x80x9d, p. 59-120, Academic Press, NY, 1967.
The tetrazole may be formed from the nitrile at various stages of the synthesis by treatment with hydrazoic acid formed in situ from sodium azide and an acid.
When B is xe2x80x94N(R20)C(O)xe2x80x94, or xe2x80x94C(O)N(R20)xe2x80x94 then condensation of the acid halide with the appropriate amine will give the desired compound as shown below in the following scheme. 
Those compounds where B and/or E are a chemical bond may also be synthesized by coupling methods analogous to those for compounds where A is a chemical bond as described above.
Furthermore, compounds of the invention may be easily synthesized by solid phase methods, as outlined below, using imputs (XI)-(XVII) as listed in schemes 105 and Table 3 below: 
Similarly, other compounds of the invention can be made by a skilled person using the above mentioned methodology.
Compounds useful according to the invention also may be prepared by the application or adaptation of other known methods, by which is meant methods used heretofore or described in the literature, for example those described by R. C. Larock in Comprehensive Organic Transformations, VCH publishers, 1989.
In the reactions described hereinafter, it may be necessary to protect reactive functional groups, for example, hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, so as to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice. For examples, see T. W. Green and P. G. M. Wuts in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d John Wiley and Sons, 1991; and J. F. W. McOmie in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d Plenum Press, 1973.
According to a further feature of the present invention, compounds useful according to the invention may be prepared by interconversion of other compounds of the invention.
A compound of the invention that includes a group containing at least one nitrogen ring atom, preferably imine (xe2x95x90Nxe2x80x94), may be converted to the corresponding compound wherein at least one nitrogen ring atom of the group is oxidized to an N-oxide, preferably by reacting with a peracid, for example, peracetic acid in acetic acid or m-chloroperoxybenzoic acid in an inert solvent such as dichloromethane, at a temperature from about room temperature to reflux, preferably at elevated temperature.
The products of this invention may be obtained as racemic mixtures of their dextro and levorotatory isomers, since at least one asymmetric carbon atom may be present. When two asymmetric carbon atoms are present, the product may exist as a mixtures of diastereomers based on syn and anti configurations. These diastereomers may be separated by fractional crystallization. Each diastereomer may then be resolved into dextro and levorotatory optical isomers by conventional methods.
It will also be apparent to those skilled in the art that certain compounds of Formula I may exhibit geometrical isomerism. Geometrical isomers include the cis and trans forms of compounds of the invention having an alkenyl moiety. The present invention comprises the individual geometrical isomers and stereoisomers and mixtures thereof.
Such isomers can be separated from their mixtures, by the application or adaptation of known methods, for example chromatographic techniques and recrystallization techniques, or they are separately prepared from the appropriate isomers of their intermediates, for example, by the application or adaptation of methods described herein.
Resolution may best be carried out in the intermediate stage where it is convenient to combine the racemic compound with an optically active compound by salt formation, ester formation, or amide formation to form two diasteromeric products. If an acid is added to an optically active base, then two diastereomeric salts are produced which possesses different properties and different solubilities and can be separated by fractional crystallization. When the salts have been completely separated by repeated crystallization, the base is split off by acid hydrolysis, and enantiomerically purified acids are obtained.
Compounds useful according to the invention are useful in the form of the free base or acid or in the form of a pharmaceutically acceptable salt thereof. All forms are within the scope of the invention.
Where a compound useful according to the invention is substituted with a basic moiety, acid addition salts are formed and are simply a more convenient form for use; in practice, use of the salt form inherently amounts to use of the free base form. The acids which can be used to prepare the acid addition salts include preferably those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial pharmaceutical effects of these compounds in the free base are not vitiated by side effects ascribable to the anions. Although pharmaceutically acceptable salts of said basic compounds are preferred, all acid addition salts are useful as sources of the free base form even if the particular salt, per se, is desired only as an intermediate product as, for example, when the salt is formed only for purposes of purification, and identification, or when it is used as an intermediate in preparing a pharmaceutically acceptable salt by ion exchange procedures. Pharmaceutically acceptable salts useful within the scope of the invention are those derived from the following acids: mineral acids, such as hydrochloric acid, trifluoroacetic acid, sulfuric acid, phosphoric acid and sulfamic acid; and organic acids, such as acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesufonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid, and the like. The corresponding acid addition salts comprise: hydrohalides, e.g., hydrochloride and hydrobromide, trifluoroacetates, sulfates, phosphates, nitrates, sulfamates, acetates, citrates, lactates, tartarates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-xcex2-hydroxynaphthoates, gentisates, mesylates, isothionates, di-p-toluyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates and quinates, respectively.
The acid addition salts of the compounds useful according to the invention are prepared by reaction of the free base with the appropriate acid, by the application or adaptation of known methods. For example, the acid addition salts of the compounds of this invention are prepared either by dissolving the free base in aqueous or aqueous-alcohol solution or other suitable solvents containing the appropriate acid, and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
The compounds useful according to the invention may be regenerated from the acid addition salts by the application or adaptation of known methods. For example, parent compounds useful according to the invention can be regenerated from their acid addition salts by treatment with an alkali, e.g., aqueous sodium bicarbonate solution or aqueous ammonia solution.
Where a compound useful according to the invention is substituted with an acidic moiety, base addition salts may be formed, and are simply a more convenient form for use; in practice, use of the salt form inherently amounts to use of the free acid form. The bases which can be used to prepare the base addition salts include preferably those which produce, when combined with the free acid, pharmaceutically acceptable salts, that is, salts whose cations are non-toxic to the animal organism in pharmaceutical doses of the salts, so that the beneficial pharmaceutical effects on the activity of the compounds of the present invention in the free acid are not vitiated by side effects ascribable to the cations. Pharmaceutically acceptable salts useful according to the invention, include for example alkali and alkaline earth metal salts, including those derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, omithine, choline, N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, diethylamine, N-benzylphenethylamine, piperazine, tris(hydroxymethyl)aminomethane, tetramethylammonium hydroxide, and the like.
Metal salts of compounds useful according to the present invention may be obtained by contacting a hydride, hydroxide, carbonate or similar reactive compound of the chosen metal in an aqueous or organic solvent with the free acid form of the compound. The aqueous solvent employed may be water or it may be a mixture of water with an organic solvent, preferably an alcohol such as methanol or ethanol, a ketone such as acetone, an aliphatic ether such as tetrahydrofuran, or an ester such as ethyl acetate. Such reactions are normally conducted at ambient temperature but they may, if desired, be conducted with heating.
Amine salts of compounds useful according to the present invention may be obtained by contacting an amine in an aqueous or organic solvent with the free acid form of the compound. Suitable aqueous solvents include water and mixtures of water with alcohols such as methanol or ethanol, ethers such as tetrahydrofuran, nitrites such as acetonitrile, or ketones such as acetone. Amino acid salts may be similarly prepared.
The base addition salts of the compounds useful according to the invention can be regenerated from the salts by the application or adaptation of known methods. For example, parent compounds useful according to the invention can be regenerated from their base addition salts by treatment with an acid, e.g. hydrochloric acid.
Salt forms useful according to the invention also include compounds having a quarternarized nitrogen. The quarternarized salts are formed by methods such as by alkylation of sp3 or sp2 hybridized nitrogen in the compounds.
As will be self-evident to those skilled in the art, some of the compounds useful according to the invention do not form stable salts. However, acid addition salts are most likely to be formed by compounds useful according to the invention having a nitrogen-containing heteroaryl group and/or wherein the compounds contain an amino group as a substituent. Preferable acid addition salts of the compounds useful according to the invention are those wherein there is not an acid labile group.
As well as being useful in themselves as active compounds, the salts of the compounds useful according to the invention are useful for the purposes of purification of the compounds, for example by exploitation of the solubility differences between the salts and the parent compounds, side products and/or starting materials by techniques well known to those skilled in the art.
Various substituents on the compounds useful according to the invention, e.g., as defined in R, R1 and R2, can be present in the starting compounds, added to any one of the intermediates or added after formation of the final products by known methods of substitution or conversion reactions. If the substituents themselves are reactive, then the substituents can themselves be protected according to the techniques known in the art. A variety of protecting groups known in the art may be employed. Examples of many of these possible groups may be found in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d by T. W. Green, John Wiley and Sons, 1981. For example, nitro groups can be added to the aromatic ring by nitration, and the nitro groups then converted to other groups, such as amino, by reduction, and halo, by diazotization of the amino group and replacement of the diazo group. Acyl groups can be substituted onto the aryl groups by Friedel-Crafts acylation. The acyl groups then can be transformed to the corresponding alkyl groups by various methods, including the Wolff-Kishner reduction and Clemmenson reduction. Amino groups can be alkylated to form mono and dialkylamino groups; and mercapto and hydroxy groups can be alkylated to form corresponding ethers. Primary alcohols can be oxidized by oxidizing agents known in the art to form carboxylic acids or aldehydes, and secondary alcohols can be oxidized to form ketones. Thus, substitution or alteration reactions can be employed to provide a variety of substituents throughout the molecule of the starting material, intermediates, or the final product.
The starting materials and intermediates are prepared by the application or adaptation of known methods, for example methods as described in the Reference Examples or their obvious chemical equivalents.